Method for coating microstructured components

ABSTRACT

The invention relates to a method for the surface modification of microstructured components having a polar surface, in particular for high-pressure applications. According to said method, a microstructured component is contacted, in particular treated, with a modification reagent, the surface properties of said component being modified by chemical and/or physical interaction of the component surface and of the modification reagent.

The present invention relates to the field of microfluidics. Inparticular, the present invention relates to a method for modifying, inparticular hydrophobing, surfaces of microstructured substrates orcomponents having polar surfaces.

The present invention also relates to a microstructured componentcomprising a surface modification. Moreover, the present inventionrelates to a microstructured component, in particular a nozzle system,of a microfluidic system having a modified surface.

Furthermore, the present invention relates to a discharge apparatus, inparticular an atomiser for fluids, preferably in the medical field.

Lastly, the present invention relates to a method for assessing surfacemodifications of microstructured components.

In medicine, atomisers are used in particular as inhalation devices fortreating respiratory diseases. For example, asthmatic diseases andchronic bronchitis are treated using inhalation therapies. For modern,specialist inhalation therapy, bronchial asthma and chronic bronchitis(also referred to as COPD chronic obstructive pulmonary disease) are themain indications. The two illnesses are “obstructive respiratorydiseases”, which account for around 90% of all respiratory diseases intotal.

With its characteristic progressive deterioration of respiratory power,chronic bronchitis is one of the main causes of invalidity and deathworldwide. In particular, complications and the associated stays inhospital mean bronchial asthma and COPD cause high costs for healthcarebudgets around the world. With instances of the diseases increasingglobally, treatment of and research into these two respiratory diseaseswill need to be high priorities in the future.

The aim of drug therapy by inhalation is to deposit an active substancein the lungs. Since many of the compounds used for the therapy may alsohave systemic effects, applying these active substances by inhalationhas many advantages over oral or intravenous administration. Ideally,only the affected organ is treated, and locally high effectiveconcentrations can be achieved. In addition, the onset of actiongenerally occurs rapidly and systemic side effects are rare. With newbronchodilators and anti-inflammatories appearing on the market over thelast few years, the situation for many asthma and COPD patients hasimproved. Yet much of this improvement is also down to innovations inthe field of device development (cf. Ambrosino, N. and P. Paggiaro, Themanagement of asthma and chronic obstructive pulmonary disease: currentstatus and future perspectives. Expert. Rev. Respir. Med., 2012. 6(1):pp. 117-127).

The success of an inhalation therapy is dependent on the amount ofmedicinal product inhaled and the distribution thereof in the airways.Their distribution is affected in many different ways by a wide range offactors. These include the characteristic properties of the aerosolitself, the inhalation device used for the application, the nature ofthe inhalation performed by the patient and the anatomy of the airways(cf. Ganderton, D., Targeted delivery of inhaled drugs: currentchallenges and future goals. J. Aerosol Med., 1999. 12 Suppl 1: pp.S3-8; Pavia, D., Efficacy and safety of inhalation therapy in chronicobstructive pulmonary disease and asthma. Respirology, 1997. 2 Suppl 1:pp. S5-10).

One particularly important property of the aerosol is its particle sizedistribution since this has a significant impact on the deposition ofaerosol particles in the airways. Aerosol particles having anaerodynamic diameter of from 2 to 5 μm perform well when inhaled intothe smaller bronchioles and peripheral airways (cf. Ariyananda, P. L.,J. E. Agnew, and S. W. Clarke, Aerosol delivery systems for bronchialasthma. Postgrad. Med. J., 1996. 72(845): pp. 151-156). By contrast,relatively large particles collide with the upper airways while smallerparticles in turn end up in the alveoli and some may even be exhaledagain.

To apply a medicinal product by inhalation, many portable devices areavailable (also referred to as devices or inhalers). These includepressurised metered dose inhalers (pMDI), which are operated usingchlorofluorocarbons (CFC) or hydrofluoroalkanes (HFA), and dry powderinhalers (DPI). For many years, CFC-MDI inhalers formed the basis forbronchial asthma and chronic bronchitis treatment. However, manypatients had trouble using this inhaler group and did not receive theoptimum therapeutic effect in their inhalation therapy. The limitationsof pMDIs and the movement towards environmentally friendly,propellant-free inhalers have sped up the development of new inhalationdevices.

According to Ganderton (see above), an optimum inhalation device meetsthe following requirements:

-   -   high deposition of active ingredient in the lungs    -   slow aerosol discharge    -   simple to handle inhalation device    -   feedback to patient after dose administered    -   presence of a meter or content indicator    -   convenient format    -   environmentally friendly    -   reusable.

When Boehringer Ingelheim brought the Respimat® Soft Mist™ inhaler ontothe market in 2003, a new inhalation device that met a large number ofthe above requirements became available. The Respimat® Soft Mist™inhaler is a propellant-free atomiser that produces the aerosol usingthe mechanical energy of a spring and the collision of two liquid jets.Owing to its different principle for generating the aerosol, the inhalercould not be assigned to any of the above categories of inhalationdevices; instead, it created a new type of inhalation device: soft mistinhalers (SMI). The aerosol cloud of an SMI is slower than that of apMDI or DPI and has a much higher fine particle fraction (FPF). Owing tothe relatively long duration of spray, the patient can coordinate theinhalation of the aerosol effectively and the relatively high fineparticle fraction makes the deposition thereof in the deeper airwaysvery efficient. The high fraction of respirable aerosol particles makesit possible to reduce the dose applied and thus reduces the likelihoodof undesired medicinal product effects occurring (cf. Dalby, R., M.Spallek, and T. Voshaar, A review of the development of Respimat SoftMist Inhaler. Int. J. Pharm., 2004. 283(1-2): pp. 1-9). WO 91/14468 A1discloses an SMI-type apparatus for the propellant-free administrationof a metered amount of a liquid medicinal product to be inhaled.

Compared with other inhalation methods in the prior art, therefore,SMI-type devices or inhalers allow respiratory diseases to be treated ina much more efficient and gentle manner. WO 2009/047173 A2 discloses anexample of an SMI device. In the atomiser described therein, liquidmedicinal product formulations are stored in a container and conveyedinto a pressure chamber through a conveying tube in order to eventuallybe emitted through a nozzle. The nozzle has a liquid inlet side and aliquid outlet side. On the liquid inlet side, there is an openingthrough which a liquid from the pressure chamber can enter the nozzle.On the opposite side, the liquid then exits through two nozzle openingsthat are oriented such that the liquid jets exiting the openings collidewith one another and are atomised as a result. This atomisationprinciple will be referred to as “double jet impinging” (DJI) in thefollowing.

SMI-type inhalers are suitable for discharging liquid formulations,preferably based on water or water-ethanol mixtures. Within a fewseconds, preferably over a time period or duration of spray of from 1 to2 seconds, they can atomise a small amount of a liquid formulation intoan aerosol suitable for inhalation therapy at the necessary therapeuticdoses. By means of this device, amounts of less than 100 μl, preferablyless than 20 μl, can be atomised into an aerosol using such a stroke,for example, that the inhalable proportion is preferably more than 60%and/or actually corresponds to the therapeutically effective amount.

Using the SMI-type inhalers being discussed here, a medicinal productsolution is transformed, by means of a high pressure (preferably morethan 50 bar) of up to 1000 bar, preferably of up to 300 bar, into alow-speed, respirable aerosol cloud that can be inhaled by the patient.

When using inhalers having small nozzle openings, the nozzle outlets canin rare cases become blocked by formulation solution residues adheringto the nozzle outlets as impurities when the atomiser is being used.This leads to the liquid jets being deflected and, in particular whenDJI nozzles are used, to a change in the fine particle fraction.Precipitation of particles in the region of micronozzles can lead to thenozzle becoming blocked or clogged, which has an adverse effect on thefunctioning of the atomiser. This phenomenon is summarised below by theterm “jet divergency”. It goes without saying that the occurrence ofthis effect is dependent on the constituents and compositions of theformulations. In general, however, it would also be desirable to reducenozzle blockages, which often occur due to particle accumulations, informulations for which this effect is more likely than in others. Theoccurrence of accumulations is known, for example, from microfluidicsystems containing free-flowing suspensions.

The occurrence of clogging in microchannels is a complex phenomenon. Thepotential mechanisms include the particles binding to the channel wallsurface due to the presence of attraction forces and the subsequentclogging by accumulations in the flow path or by “hydrodynamicbridging”. Hydrodynamic bridging refers to the phenomenon wherebyparticles smaller than the channel diameter reach a constriction at thesame time and then block said constriction. The effect depends on boththe colloidal repulsion forces and the tensile force applied. Particlesare transported to the channel wall e.g. by inertia forces, Brownianmotion, sedimentation or interception. The effectiveness of theparticles binding always depends on the ratio of attraction andrepulsion forces.

It is desirable, for example, to extend the range of application of SMIsand DJI nozzle technology to include complex formulations, for examplethose based on ethanolic solvents. Beneficial applications in thisregard are in the field of inhalation corticoid therapy. In the field ofhighly effective corticosteroids specifically, the option to use an SMIto transform small amounts of formulation into a slow spray cloud wouldmean more effective inhalation can be expected than is currently thecase in conventional inhalation devices.

The basic pharmacological therapy for bronchial asthma involves aninhaled corticosteroid (ICS) containing a long-acting P₂ agonist (LABA)being administered alone or in combination with other substances. Thefirst choice in drug therapy for chronic bronchitis is the soleadministration of a bronchodilator from the range of LABAs and LAMAs(long-acting antimuscarinic antagonists). Depending on the sensitivityof the COPD to a corticoid therapy, however, therapy with an ICS is alsopossible.

Expanding inhalation therapy by means of SMI or DJI technology would bedesirable in general since it would allow drugs to be administered in agentler and more effective manner. In this case, however, and inparticular with complex formulations, the problem is that activeingredients adhere to the inhaler and can thus lead to the spray patterndeteriorating and ultimately to a nozzle blockage.

In addition, medicinal product formulations having long-term stabilityoften have pHs that can cause reactions within the inhaler and forexample the precipitation of poorly soluble compounds, which can in turncause nozzle blockages due to particle adhesion.

Since the use of SMI-type inhalers could further reduce the occurrenceof undesirable medicinal product effects, there have been many testscarried out on preventing particle adhesion and expanding the use ofSMI-type inhalers and DJI-type nozzles.

To prevent impurity particles adhering in the region of the nozzleopenings, WO 2004/089551 A1 discloses a microstructure or nanostructurefor DJI-type nozzles and SMI-type inhalers, in which the outer surfaceof the liquid outlet side is microstructured or nanostructured.

In addition, WO 2010/112358 A2 discloses a method for coating an inparticular microstructured surface of a component that consists ofdifferent materials, in particular glass and silicon, and the surface ofwhich is first activated and then coated. The component is preferably aDJI nozzle that can be used in SMI-type inhalers. The component surfaceis activated by an oxidising solution, a basic solution or an acidicoxidising solution.

By means of the aforementioned methods and modifications to DJI nozzles,clogging or blockage of the nozzle outlet openings can be delayed or insome cases prevented. However, some of these methods are very complexand expensive, in particular in the case of the microstructured outletopenings according to WO 2004/089551 A1, or often do not reliably leadto the desired results.

The object of the present invention is therefore to mitigate or at leastsubstantially to prevent the aforementioned problems that occur in theprior art.

In addition, another object of the present invention is to provide animproved nozzle system for the propellant-free discharge of liquids frominhalers that allows for the use of a wider range of active ingredientcombinations, achieves considerably better use and performanceproperties and in particular has self-cleaning properties, as well asproviding a method by which the use properties of nozzles can beimproved and in particular self-cleaning properties on nozzles can beachieved or surface properties of nozzles can be altered.

Another object of the present invention is to expand the range of use ofinhalers, in particular SMI-type inhalers.

According to a first aspect of the present invention, the presentinvention relates to a method for modifying surfaces of microstructuredsubstrates according to claim 1; the related dependent claims set outadditional advantageous embodiments of this aspect of the invention.

According to a second aspect of the present invention, the presentinvention relates to a microstructured component according to eitherclaim 62 or claim 63; the related dependent claims set out additionaladvantageous embodiments of this aspect of the invention.

According to a further aspect of the present invention, the presentinvention relates to a fluid discharge apparatus according to claim 77;the related dependent claims set out additional advantageous embodimentsof this aspect of the invention.

Lastly, according to a further aspect of the present invention, thepresent invention also relates to a method for assessing the surfacemodification as a microstructured component according to claim 85; therelated dependent claims set out additional advantageous embodiments ofthis aspect of the invention.

It goes without saying that, in order to avoid repetitions, specialcharacteristics, features, designs and embodiments, and advantages orthe like set out below in relation to just one aspect of the inventionapply mutatis mutandis to the other aspects of the invention, withoutthis having to be specifically mentioned.

It is also self-evident that no values, numbers or ranges set out belowshall be construed as being limiting; instead, a person skilled in theart may of course deviate from the stated ranges or details inindividual cases or applications, without departing from the scope ofthe present invention.

In addition, all the values, parameters or the like stated in thefollowing can be determined or defined using standardised or explicitlystated determination methods or determination methods that are routinefor a person skilled in the relevant art.

Moreover, it goes without saying that a person skilled in the art knowsthey can select all weight-based or volume-based percentage values insuch a way as to come to a total of 100%; this is self-evident.

On this basis, the present invention will now be described below in moredetail.

According to a first aspect of the present invention, the presentinvention thus relates to a method for modifying, in particularhydrophobing, surfaces of substrates or fluidic components, inparticular microstructured components (such as nozzle bodies), havingpolar surfaces, in particular for high-pressure applications, asubstrate or microstructured component being brought into contact, inparticular treated, with a modification reagent, the surface propertiesof the substrate being modified by chemical and/or physical interactionbetween the component surface and the modification reagent, themodification reagent comprising at least one modifier and the modifierbeing selected from the group consisting of silanes, siloxanes,polysiloxanes and/or siliconates and mixtures thereof.

Within the context of the present invention, by modifying the surface ofsubstrates or microstructured components, it has been possible to modifythe surface properties thereof such that the adhesion of substances, inparticular of residues of liquid solutions or dispersions conducted overor through the microstructured substrate or component, can be increasedor reduced as required.

Within the context of the present invention, it is possible, by coatingthe substrate or microstructured component, in particular to manipulatethe surface properties of the substrate or component in a targetedmanner such that the interaction between the substrate or componentsurface and the substances, in particular fluids conducted over thesurface, can be altered or reduced in a targeted manner.

Within the context of the present invention, it is possible inparticular to reduce the wetting of the substrate surface by fluidsconducted through or over the substrate. This is done in particular byhydrophobing the surface, i.e. the surface is preferably treated with ahydrophobic substance, as a result of which the surface energy of thesubstrate is reduced in particular and hydrophilic substances can nolonger interact with the surface to the same extent as before.

Within the context of the present invention, treating the surface withthe modification reagent should be taken to mean that the physicaland/or chemical properties of the substrate surface are altered.

The substrate or microstructured component can be treated with themodification reagent in any suitable manner. Usually, however, thesubstrate is brought into contact with a solution or dispersion of themodification reagent, in particular is sprayed with or dipped into asolution or dispersion of the modification reagent.

In particular, within the context of the present invention, the surfacemodification is surprisingly able to bring excellent results even inhigh-pressure applications. The surface modification obtainable usingthe method according to the invention is not usually damaged ordestroyed even at high pressures of up to 1,000 bar, in particular atpressures in the range of from 50 to 1,000 bar, in particular from 200to 600 bar, preferably from 250 to 350 bar (tested for laminar flowsrunning substantially in parallel with the modified surface).

Within the context of the present invention, the polar surface of themicrostructured substrate is preferably formed by polar functionalchemical groups. Within the context of the present invention, polarfunctional chemical groups should be understood to be chemicalfunctional groups such as hydroxy groups, ester groups, carbonyl groups,amine groups, sulphane groups or similar groups that have a permanentdipole moment and render the surface of the microstructured substratereceptive in particular to interaction with other polar groups.

Within the context of the present invention, microstructured componentsshould be understood in particular to be components that comprise, ontheir outer or inner surfaces, structures, e.g. in the form of channelsor reliefs, having an extension in at least one spatial direction of nomore than 100 μm, in particular no more than 50 μm, preferably no morethan 20 μm, particularly preferably in the range of from 2 μm to 8 μm.Within the context of the present invention, it is possible to modifythe surface properties of particularly fine microstructures whileretaining the shape of the structure and not covering the shape orreducing the contour sharpness thereof by transformation using a coatingreagent or by applying a coating.

Within the context of the present invention, the microstructuredcomponent can comprise at least two different materials. Where, withinthe context of the present invention, the microstructured componentcomprises at least two different materials, these materials usually eachhave polar surfaces.

Within the context of the present invention, it has also proveneffective for all the materials of the microstructured component to havepolar surfaces.

Within the context of the present invention, the surfaces of thematerials of the component are generally modified together. Modifyingthe component surfaces together or simultaneously results in aparticularly simple and quick modification since each material does nothave to be hydrophobed separately. Coating together or simultaneouslyshould be understood to mean that the various materials of the componentare modified together preferably in terms of time and/or location. Thismeans that the various materials of the component are preferably firstinterconnected and then the surface of this composite is modified, inparticular by transformation using a modification reagent or modifier.

As regards the material that can be used for the microstructuredcomponent within the context of the present invention, it has proveneffective for the component to comprise glass, in particular silicateglass, preferably quartz glass and/or borosilicate glass, preferablyborosilicate glass, e.g. in the form of a cover on microstructures.Glass, in particular silicate glass, is a shape-retaining, sturdy,chemically inert material. In particular, glass does not usually reactwith organic compounds as contained in drugs or pharmaceuticalcompositions for example.

In addition, good results have also been achieved within the context ofthe present invention if the component comprises silicon, in particularelementary silicon. Where the component comprises elementary silicon, ithas proven effective for at least part of the component to consist of orcontain a silicon wafer. Elementary silicon has a polar surface sincesilicon, as a base metalloid, is always covered with a thin native oxidelayer. This oxide layer is exceptionally capable of binding modificationreagents or modifiers. In addition, silicon can be produced onmicrostructures very effectively, i.e. microstructures can be applied tosilicon, in particular silicon wafers, in a simple manner. This can bedone, for example, by established methods in semiconductor technologysuch as etching.

Within the context of the present invention, particularly good resultsare obtained if the component comprises, in particular consists of,elementary silicon and glass. Within the context of the presentinvention, therefore, it is preferable for the microstructured componentto consist of glass and elementary silicon that in particular has anative oxide layer.

As regards the shape of the materials used for the component, this canvary greatly. However, it has proven effective for the differentmaterials of the component to be in particular at least substantiallysquare, preferably plate-like. Preferably, the different materials ofthe component are glass wafers and/or silicon wafers. Having thematerials in a square or plate-like design makes mechanical processingsimpler and allows the materials to be connected in a simple manner.Since the materials are usually connected via their largest surfaces,very sturdy composites can be obtained, in particular in the case ofplate-like materials such as wafers.

Within the context of the present invention, the materials of themicrostructured component can be connected in any conceivable manner,the aim being to obtain a bonded composite that is impermeable to bothgases and liquids. Preferably, the different materials, in particularthe glass and silicon wafers, are rigidly interconnected, for exampleglued, pressed or connected by means of “bonding”. For further detailson the bonding, reference is made here to European patent document EP 1644 129 B1.

Within the context of the present invention, the different materials arepreferably interconnected without joining agents such as adhesives,since using joining agents may leave residues in the microstructures ofthe component and thus the component may function less effectively ornot at all.

It has been found that the method according to the invention can also beapplied to the surface modification of substrates or components havingany form of microstructure. Good results are obtained for componentshaving microstructures in the form of channels. In this respect, thechannels can have a diameter in the range of from 0.1 to 50 μm, inparticular from 0.5 to 40 μm, preferably from 1 to 20 μm, preferablyfrom 2 to 15 μm, particularly preferably from 2.5 to 10 μm, mostpreferably from 3 to 8 μm. The method according to the invention allowsfor the surfaces of very fine microstructures to be modified, inparticular coated, without the contour sharpness of the microstructuresbeing lost or reduced. Within the context of the present invention, thechannels of the microstructured component should be understood to bechannels within the microstructured component.

As regards making the microstructures in the component or componentsurface, these can likewise be made in many different ways. Within thecontext of the present invention, however, the microstructures areusually made in at least one of the component materials. In this regard,the microstructures can be made in at least one of the componentmaterials by for example drilling, milling, laser cutting or etching,preferably by etching. Preferably, elementary silicon is provided withmicrostructures. Where elementary silicon is used, the microstructure ispreferably made in the component material by etching. In silicon, finemicrostructures can be made on a large scale and in a particularlysimple manner using etching technology. To produce internal surfaces,i.e. cavities, such as channels, in the microstructured component, themicrostructure is preferably made in the surface of one of the componentmaterials, in particular in elementary silicon, and then the material isjoined to a second material, in particular glass, such that themicrostructure is covered by the second material and is located withinthe composite material or the “sandwich composite”.

Within the context of the present invention, the component is generallya microfluidic system. The microstructured component thus preferablycomprises channels or cavities that have a diameter of just a fewmicrometres and through which fluids are conducted. A particular featureof microfluidics is that fluids, in particular liquids and gases,preferably liquids, behave differently in narrow spaces than macroscopicfluids. For example, frictional forces often play a bigger role inmicrofluidic systems than in macroscopic systems. Capillary forces andthe interaction between the fluid and the surface of the microfluidicsystem are also of much greater significance than in macroscopicsystems, for example. In this way, it is possible for the use propertiesof microstructured components to be significantly altered by surfacemodification. Within the context of the present invention, microfluidicsystems are also preferred since, in particular in medicinal productapplications, especially low amounts of highly potent medicinal productshave to be discharged and atomised in as uniform a manner as possible.

According to the basic principle, microfluidic systems can be dividedinto five different groups in principle. These are capillary-drivensystems, pressure-driven systems, centrifugally-driven systems,electrokinetic systems and acoustically driven systems. In thefollowing, some examples will be briefly explained.

In capillary-driven systems, such as lateral flow tests (LAT), alsoreferred to as “test strips”, e.g. pregnancy test strips, the liquid istransported by means of capillary forces present.

By contrast, in “linear actuated devices”, which come underpressure-driven systems, the liquid is moved by mechanical dislocation(e.g. a pump plunger). In this case, the movement of the liquid is oftenrestricted to one direction. This technology is integrated veryfrequently with calibration solutions and reaction buffers.

Centrifugally-driven systems, also known as centrifugal microfluidics,use inertia and capillary forces present in the system. Relevant inertiaforces in this case are centrifugal force, Euler forces and Coriolisforces. The basic substrates are often discoid and the active liquidtransport is generally directed outwards.

Electrokinetic systems use electrical charges, electrical fields,electrical field gradients or temporarily fluctuating electrical fields.This is made possible by using electrodes, making it possible for thewide range of effects (electrophoresis, dielectrophoresis, osmotic flow,polarisation) to be superimposed on one another depending on the liquidused.

Acoustically driven systems are, for example, surface acoustic wavesintended for liquid transport. Surface acoustic waves (SAW) should beunderstood to be acoustic shock waves on a solid surface. An acousticshock wave generates a pressure when it impinges on a droplet. If thispressure exceeds a critical value, the droplet moves on the substratesurface. Generally, the solid surface is generally coated so as to behydrophobic and thus simplifies the droplet movement. By positioningvarious SAW sources on a substrate, the movement of the droplet on thesubstrate can be designed as desired.

Preferably, the microfluidic system used within the context of thepresent invention is a pressure-driven microfluidic system, preferably anozzle system for an SMI-type inhaler, as described below. Due to itsmicrofluidic component being the nozzle body, which preferably includeschannel, filter and nozzle structures, the inhaler described belowbelongs to the group of pressure-driven systems, in particular to linearactuated devices.

As regards the design of the microstructured component, this canlikewise vary widely. However, for the preferred application accordingto the invention it has proven effective for the component to compriseat least one inlet opening and at least one outlet opening, preferablytwo outlet openings, for fluids, in particular for liquids. The inletand outlet openings are preferably connected, i.e. within the componentthere are cavities and channels through which preferably a fluid, inparticular a liquid, preferably a liquid pharmaceutical composition, canbe conducted.

Within the context of the present invention, particularly good resultsare obtained if the outlet openings form nozzles for discharging aliquid. Within the context of the present invention, the outlet openingspreferably form nozzles through which a liquid, in particular a liquidpharmaceutical composition, is conducted out of the microstructuredcomponent, in particular pressed out under pressure, preferably sprayed.The liquid is preferably atomised when it exits the outlet openings orthereafter; this can be done for example by using specifically designednozzles or by liquid jets impinging on one another as they exit thenozzles (for example in the DJI nozzles preferred in this case).

According to a preferred embodiment of the present invention, thecomponent comprises a filter region between the inlet opening and outletopening(s). By means of a filter region, it is possible for relativelylarge particles located for example within a liquid reservoir storingthe liquid to be discharged, in particular the pharmaceuticalcomposition, to be kept away from the outlet openings, in particularfrom the nozzles, such that the nozzles do not become clogged byrelatively large particles or the liquid jet exiting the outlet openingsis not deflected.

Within the context of the present invention, the inner surface of thecomponent is usually in particular at least substantially modified.Within the context of the present invention, preferably the entire innersurface of the component is modified. In this regard, however, it isparticularly important for the channels that open into the outletopenings, in particular into the nozzles, to be modified such as toprevent deposits in this region that quickly lead to the nozzlesnarrowing and thus to the spray pattern changing. In addition, nozzlesshould be prevented from becoming blocked or clogged as far as possible.

Within the context of the present invention, an inner surface of themicrostructured component should be understood to be the surface withinthe microstructured component that is formed by cavities such aschannels and nozzles. These cavities form the microfluidic systemthrough which fluids, in particular liquids, are conducted in order toultimately be atomised.

According to a preferred embodiment of the present invention, the outersurface of the component is also modified, in particular in the regionof the outlet openings. Modifying the outer surface of the component, inparticular in the region of the outlet opening, i.e. in the nozzleregion, also prevents particles or dried constituents of the dischargedliquid from being deposited.

Within the context of the present invention, the outer surface of themicrostructured component should be understood to be the outer surfaceof the microstructured component, i.e. the surface that is usuallyvisible from the outside.

Within the context of the present invention, inner surfaces can beproduced, for example, by providing the outer surface of a material orof a first component part with a microstructure and then applying anadditional material or a second component part to this first material,in particular to the microstructure produced (e.g. in the form of acover). As a result, the outer microstructure of one material or of thefirst component part becomes an inner microstructure of the compositematerial or component.

Within the context of the present invention, the entire surface, i.e.the inner and outer surfaces, can be modified.

Within the context of the present invention, it is possible for theproperties of the component surface to be adjusted in a targeted mannerby the surface modification, in particular by the hydrophobing. Withinthe context of the present invention, the properties of the componentsurface can be adjusted in particular by selecting a suitable modifieror modification reagent.

In this respect, the modification reagent can be brought into contactwith the surface of the substrate or component in any conceivablemanner. Particularly good results are obtained, however, if bringing themodification reagent into contact with the surface of the substrateapplies a layer, in particular a hydrophobing layer, to the surface ofthe substrate or component.

In this case, a layer within the context of the present invention shouldbe understood to be not only the binder layer, such as a paint layerusually having a thickness of several micrometres, but also amonomolecular layer, which consists of a single molecule layer(“monolayers”).

A layer of this kind is often also referred to as a surfacefunctionalisation or modification, in particular when the layer is inthe form of a monolayer or is formed as a monolayer. Within the contextof the present invention, it is possible for the modification, inparticular the coating, to be repeated multiple times such that aplurality of layers are applied. However, it is preferable for only onecoating method step to be carried out, i.e. for just one layer, inparticular a monolayer, to be applied.

Within the context of the present invention, particularly good resultsare obtained if the layer is applied to the substrate or component inthe form of a monolayer. Applying monolayers makes it possible toachieve extremely thin coatings, i.e. a minimum amount of coating agentor modifier is used. Where, within the context of the present invention,the layer is applied to the substrate or component in the form of amonolayer, the monolayer is usually applied to the substrate orcomponent as a “self-assembled monolayer” (SAM). Applying the layer inthe form of a monolayer is advantageous in that the complete shape ofthe structures of the components is retained and contour sharpness isnot lost as a result of the coating agent or modifier.

The layer applied to the substrate or component should preferably be sothin as to prevent any changes to the geometry or topology of themicrostructures and such that their contour sharpness is retained.Usually, deposits as a result of particles occur in the front region ofthe channel structures, for example in the region of the nozzle bodies.Therefore, the coatings should be sufficiently thin for the channelgeometries to be unchanged or only changed to a minor extent in thisregion. In addition, sufficient mechanical stability is essential forwithstanding the strong forces during application. To produce thinlayers or monolayers, a multiplicity of methods can be used. Usually,the Langmuir-Blodgett method is used (preferred for planar substrates;as regards the production and characterisation of “Langmuir films”,reference is merely made here to the relevant prior art, e.g. Paso, K.,et al., Hydrophobic monolayer preparation by Langmuir-Blodgett andchemical adsorption techniques. Journal of Colloid and InterfaceScience, 2008. 325(1): pp. 228-235) as well as adsorption from a gasphase or, as preferred in this case, from a produced solution (“solutionadsorption”). The layers produced using the latter method are alsoreferred to as SAMs. In the following, the production of self-assembledmonolayers by means of liquid coating will be described in more detail.To coat a composite material as preferably used within the context ofthe present invention and which is often also referred to as a sandwichsystem, the solution adsorption method is usually the most suitablemethod since it allows for uniform precipitation of molecules in acomplex microstructure owing to its excellent ability to penetratecracks. In addition, capillary effects generally assist wetting ofinternal microstructures by a liquid modification reagent.

A self-assembled monolayer is a single layer of an organic moleculeapplied to a solid substrate from a liquid or gas phase. When a suitablesubstrate and organic molecule are selected, the molecules arechemically adsorbed by means of a chemical reaction with the substratesurface when the substrate is introduced into the gas or liquid phase.

When a self-assembled monolayer is formed from a liquid phase, themolecules position themselves on the substrate on the basis ofintermolecular interactions and orient themselves relative to oneanother. A monolayer having a high degree of order is thus produced.Once the monolayer is completely formed, the growth of the layer stopssince the substrate surface covered by molecules cannot continue toparticipate in the reaction. An organic ultra-thin film of this kind isreferred to as a self-assembled monolayer since it forms spontaneouslyin a self-organising manner. The two-dimensional arrangement of the SAMsis formed in processes in which the system reached a state ofequilibrium. This means that SAMs can indeed come very close to athermodynamically stable state.

Practical examples of substrate materials in the combination ofsubstrates and organic molecules are aluminium oxide, silver oxide orglass, gold, silver, copper or gallium arsenide and silicon oxide,titanium oxide or other oxides. Related examples of organic molecules incombination with substrates are carboxylic acids, organic sulphurcompounds such as thiols, or (other) organic components. A typicalcombination is, for example, gold as a substrate material with thiol.

Since the molecules adsorb on the surface over the entire surface areaof the substrate surface, it is possible to modify the surfaceproperties of the substrate as desired, depending on the selection ofthe end terminal group. This relates not only to reducing the freesurface energy by selecting an alkyl or fluoroalkyl group but can alsorelate to the reactivity thereof as a result of the selection of e.g. anamino or epoxy group.

Linking the bond (a siloxane bond in the case of a silicon-containingsubstrate) provides organosilane SAMs with stability of a covalentnature. The bond is not only linked to the surface, but, depending onthe molecule selection, can also be linked to the neighbouringmolecules, such as to produce a bond network (a siloxane network in thecase of a silicon-containing substrate). It is for this reason thatorganosilane SAMs are considerably more stable than other SAMs in termsof mechanical strength and chemical stability.

Therefore, they provide the greatest number of possibilities in terms ofpractical use as regards the surface modification or surfacefunctionalisation.

The thickness of an SAM is often just 1 to 2 nm and depends on themolecule length. SAMs are advantageous in that, unlike comparably largepolymers, they do not vary in terms of molecule size as is common inpolymers. As regards preventing adhesion in microstructures by means ofsurface modification, SAMs are thus the coatings preferably used withinthe context of the present invention.

As regards the layer thickness of the layer applied to the substrate orcomponent, this can vary in particular according to the combination ofsubstrate material and organic molecules. For example, the layerthickness may be influenced not only by the length of the molecules usedfor the coating, but also by their spatial arrangement on the surfaceand/or the formation of a plurality of molecule layers on top of oneanother. Within the context of the present invention, however,particularly good results are obtained if the layer is applied to thesubstrate or component at a layer thickness of from 0.1 to 200 nm, inparticular from 0.2 to 100 nm, preferably from 0.3 to 50 nm, preferablyfrom 0.4 to 10 nm, particularly preferably from 0.5 to 5 nm.

Within the context of the present invention, the layer is usually boundto the substrate or component by means of chemical bonds, in particularcovalent bonds. In other words, within the context of the presentinvention, covalent bonds are formed between the modifier or coatingagent and the substrate or component surface since these allow forparticularly durable and stable compounds.

According to a preferred embodiment of the present invention, themodification reagent comprises at least one modifier, in particular atleast one of the aforementioned organosilicon compounds. The modifiercan be either an individual substance or a mixture of varioussubstances.

Within the context of the present invention, the modification reagent isa substance or substance mixture with which the component or substrateis brought into contact. The modification reagent can for example be inthe form of a solution or dispersion.

Within the context of the present invention, a modifier should beunderstood to be a chemical compound that interacts with the surfacephysically or chemically, for example by physisorption or chemisorption,and is bound to the surface of the component, possibly following achemical reaction.

Within the context of the present invention, where the surface ismodified as a coating, the modification reagent and the modifier arethus also referred to as coating reagents and coating agents.

As explained above, the modifier is selected from the group consistingof silanes, siloxanes, polysiloxanes and/or siliconates and mixturesthereof, in particular silanes, siloxanes and/or siliconates andmixtures thereof, preferably silanes.

By using silanes in particular, it is possible to achieve particularlythin layers, in particular monolayers, that also form a particularlysturdy composite with the substrate or component surface. In addition,silanes having many different organic groups can be commerciallyobtained and are also easy to manufacture, so the substrate or componentsurface can be modified by reaction with silanes as desired, inparticular can be hydrophobed as desired.

A molecule having the structure SiR_(n)X_(4-n) (R=organic group,X=reactive chemical group) is generally referred to as an organosilane.It is derived from the structure SiH₄, in which hydrogen is replaced byreactive chemical groups or organic side chains. An organic film can,for example, be formed by the functional group reacting with a hydroxygroup of an oxidised substrate or component surface.

Chlorosilanes, e.g. trichloroalkylsilanes and/or alkoxyalkylsilanes, areoften used as the starting material for the synthesis of a silane-basedlayer, in particular of an organosilane SAM. Trialkoxysilanes areprecursor compounds and have to be hydrolytically split before reactingwith the substrate or component surface. Compared with other SAMs, thereaction pathways of these compounds are relatively complex since eachmolecule has up to three reactive groups that could form a compound withthe surface or one another. To provide the silanol intended for thereaction with the substrate or component surface, a small proportion ofwater is necessary since this is usually based on a hydrolysis reactionof the chlorine groups or alkoxy groups. Next, these silanol moleculesreact with free hydroxy groups of the substrate or component surface,and the siloxane scaffold can be formed via a condensation reaction;this process is also referred to as chemisorption. Following thisreaction, the molecules are immobilised on the surface. Since eachmolecule carries a plurality of reactive groups, the siloxane bond islinked not only to molecules on the substrate or component surface, butalso horizontally between adjacent molecules. This horizontalpolymerisation plays a significant role in the two-dimensionalarrangement of an organosilane self-assembled monolayer and generatesthe stability of such a coating by means of Van der Waals forces, thehydrophobic interactions and electrostatic interactions.

Where the modifier is a siloxane, it has proven effective for themodifier to be a siloxane selected from the group consisting ofalkylsiloxanes, alkylalkoxysiloxanes, arylsiloxanes andarylalkoxysiloxanes and mixtures thereof, in particular alkylsiloxanesand alkylalkoxysiloxanes and mixtures thereof, the siloxane being analkylalkoxysiloxane.

In this regard, the siloxane can be selected from C₁-C₂₀ alkylsiloxanes,in particular C₁-C₁₅ alkylsiloxanes, preferably C₁-C₁₂ alkylsiloxanes.It is also possible for the siloxane to be selected from C₁-C₂₀alkylalkoxysiloxanes, in particular C₁-C₁₅ alkylalkoxysiloxanes,preferably C₁-C₁₂ alkylalkoxysiloxanes. In addition, the siloxane can beselected from C₆-C₂₀ arylsiloxanes, in particular C₆-C₁₈ arylsiloxanes,preferably C₆-C₁₅ arylsiloxanes. Furthermore, the siloxane can beselected from C₆-C₂₀ arylalkoxysiloxanes, in particular C₆-C₁₈arylalkoxysiloxanes, preferably C₆-C₁₅ arylalkoxysiloxanes.

Likewise, within the context of the present invention, good results areobtained if the siloxane has a weight-average molecular weight M_(w) inthe range of from 200 to 10,000 g/mol, in particular from 500 to 8,000g/mol, preferably from 700 to 5,000 g/mol, preferably from 1,000 to4,000 g/mol, particularly preferably from 1,500 to 3,000 g/mol.Therefore, where siloxanes are used within the context of the presentinvention, low-molecular-weight siloxanes are preferably used.

The siloxanes used within the context of the present invention can alsobe fluorinated, in particular partially fluorinated or perfluorinated,in order to further increase the hydrophobicity of the coating obtained.

Where, within the context of the present invention, the modifier is apolysiloxane, it has also proven effective for the modifier to be apolysiloxane selected from the group consisting of alkylpolysiloxanes,arylalkoxypolysiloxanes, arylpolysiloxanes and arylalkoxypolysiloxanesand mixtures thereof, in particular alkylpolysiloxanes andalkylalkoxypolysiloxanes and mixtures thereof, and to preferably be analkylalkoxypolysiloxane.

In this regard, the polysiloxane can be selected from C₁-C₂₀alkylpolysiloxanes, in particular C₁-C₁₅ alkylpolysiloxanes, preferablyC₁-C₁₂ alkylpolysiloxanes.

The polysiloxane can also be selected from C₁-C₂₀alkylalkoxypolysiloxanes, in particular C₁-C₁₅ alkylalkoxypolysiloxanes,preferably C₁-C₁₂ alkylalkoxypolysiloxanes.

Equally, the polysiloxane can be selected from C₆-C₂₀ arylpolysiloxanes,in particular C₆-C₁₈ arylpolysiloxanes, preferably C₆-C₁₅arylpolysiloxanes.

Furthermore, the polysiloxane can be selected from C₆-C₂₀arylalkoxypolysiloxanes, in particular C₆-C₁₈ arylalkoxypolysiloxanes,preferably C₆-C₁₅ arylalkoxypolysiloxanes.

In addition, within the context of the present invention, good resultscan likewise be obtained if the polysiloxane has a weight-averagemolecular weight M_(w) in the range of from 3,000 to 25,000 g/mol.

As regards the use of polysiloxanes, it is also possible to usepartially fluorinated or perfluorinated polysiloxanes in order toincrease the hydrophobicity of the coating.

Owing to the high molecular weight of the polysiloxanes, within thecontext of the present invention it is less preferable to usepolysiloxanes compared with the use of low-molecular-weight compounds,in particular siloxanes and silanes, preferably silanes. When selectingthe polysiloxanes, it must be ensured that, depending on themicrostructure to be coated, they can be applied to the substrate orcomponent surface in layer thicknesses that do not cover or clog themicrostructures, weaken the contour sharpness thereof, or alter theirgeometry. Within the context of the present invention, it isparticularly preferable to use silanes since silanes allow forparticularly low layer thicknesses, in particular monolayers.

Where, within the context of the present invention, a silane is used asthe modifier, a silane according to general formula I

R¹ _(4-(n+m))SiR² _(m)X_(n)  (I)

can be used, where

-   R¹=alkyl, in particular C₁-C₂₀ alkyl, preferably C₈-C₁₈ alkyl,    preferably C₁₀-C₁₆ alkyl;    -   aryl, in particular C₆-C₂₀ aryl, preferably C₆-C₁₀ aryl;    -   olefin, in particular terminal olefin, preferably C₂-C₂₀ olefin,        preferably C₈-C₁₈ olefin, particularly preferably C₁₀-C₁₆        olefin;    -   fluoroalkyl, in particular C₁-C₂₀ fluoroalkyl, preferably C₈-C₁₈        fluoroalkyl, preferably C₁₀-C₁₆ fluoroalkyl, in particular        comprising 1 to 40 fluorine atoms, preferably 5 to 35 fluorine        atoms, preferably 10 to 30 fluorine atoms;    -   fluoroaryl, in particular C₆-C₂₀ fluoroaryl, preferably C₆-C₁₀        fluoroaryl, in particular comprising 3 to 20 fluorine atoms,        preferably 5 to 20 fluorine atoms;    -   fluoroolefin, in particular terminal fluoroolefin, preferably        C₂-C₂₀ fluoroolefin, preferably C₈-C₁₈ fluoroolefin,        particularly preferably C₁₀-C₁₆ fluoroolefin, in particular        comprising 1 to 30 fluorine atoms, preferably 3 to 25 fluorine        atoms, preferably 5 to 25 fluorine atoms;-   R²=alkyl, in particular C₁-C₃ alkyl, preferably methyl;-   X=halide, in particular chloride and/or bromide, preferably    chloride;    -   alkoxy, in particular C₁-C₆ alkoxy, particularly preferably        C₁-C₄ alkoxy, most preferably C₁ and/or C₂ alkoxy; and-   n=1 to 3, in particular 3, and-   m=0 to 2, in particular 0 or 2, preferably 0.

In addition, within the scope of the present invention, the group X canalso be formed by additional reactive, in particular hydrolysable,chemical groups.

Within the context of the present invention, particularly good resultsare obtained if, for the modifier, a silane according to general formulaII

R¹ _(4-(n+m))SiR² _(m)X_(n)  (II)

Is used, where

-   R¹=alkyl, in particular C₁-C₂₀ alkyl, preferably C₈-C₁₈ alkyl,    preferably C₁₀-C₁₆ alkyl;    -   fluoroalkyl, in particular C₁-C₂₀ fluoroalkyl, preferably C₈-C₁₈        fluoroalkyl, preferably C₁₀-C₁₆ fluoroalkyl, in particular        comprising 1 to 40 fluorine atoms, preferably 5 to 35 fluorine        atoms, preferably 10 to 30 fluorine atoms;-   R²=alkyl, in particular C₁-C₃ alkyl, preferably methyl;-   X=halide, in particular chloride;    -   alkoxy, in particular C₁-C₆ alkoxy, particularly preferably        C₁-C₄ alkoxy, most preferably C₁ and/or C₂ alkoxy; and-   n=1 to 3, in particular 3, and-   m=0 to 2, in particular 0 or 2, preferably 0.

It is particularly preferable in this regard if, for the modifier, asilane according to general formula III

R_(4-n)SiX_(n)  (III)

Is used, where

-   R=alkyl, in particular C₁-C₂₀ alkyl, preferably C₈-C₁₈ alkyl,    preferably C₁₀-C₁₆ alkyl;    -   fluoroalkyl, in particular C₁-C₂₀ fluoroalkyl, preferably C₈-C₁₈        fluoroalkyl, preferably C₁₀-C₁₆ fluoroalkyl, in particular        comprising 1 to 40 fluorine atoms, preferably 5 to 35 fluorine        atoms, preferably 10 to 30 fluorine atoms;-   X=alkoxy, preferably C₁-C₄ alkoxy, most preferably C₁ and/or C₂    alkoxy; and-   n=1 to 4, in particular 3.

According to a preferred embodiment of the present invention,fluorinated silanes are used as modifiers. In this regard, good resultsare obtained if, for the modifier, a silane according to general formulaIV

R¹ _(4-(n+m))SiR² _(m)X_(n)  (IV)

Is used, where

-   R¹=fluoroalkyl, in particular C₁-C₂₀ fluoroalkyl, preferably C₈-C₁₈    fluoroalkyl, preferably C₁₀-C₁₆ fluoroalkyl, in particular    comprising 1 to 40 fluorine atoms, preferably 5 to 35 fluorine    atoms, preferably 10 to 30 fluorine atoms;    -   fluoroaryl, in particular C₆-C₂₀ fluoroaryl, preferably C₆-C₁₀        fluoroaryl, in particular comprising 3 to 20 fluorine atoms,        preferably 5 to 20 fluorine atoms;    -   fluoroolefin, in particular terminal fluoroolefin, preferably        C₂-C₂₀ fluoroolefin, preferably C₈-C₁₈ fluoroolefin,        particularly preferably C₁₀-C₁₆ fluoroolefin, in particular        comprising 1 to 30 fluorine atoms, preferably 3 to 25 fluorine        atoms, preferably 5 to 25 fluorine atoms;-   R²=alkyl, in particular C₁-C₃ alkyl, preferably methyl;-   X=halide, in particular chloride and/or bromide, preferably    chloride;    -   alkoxy, in particular C₁-C₆ alkoxy, particularly preferably        C₁-C₄ alkoxy, most preferably C₁ and/or C₂ alkoxy; and-   n=1 to 3, in particular 3, and-   m=0 to 2, in particular 0 or 2, preferably 0.

In this regard, it has proven effective if, for the modifier, a silaneaccording to general formula V

R_(4-n)SiX_(n)  (V)

is used where

-   R=fluoroalkyl, in particular C₁-C₂₀ fluoroalkyl, preferably C₈-C₁₈    fluoroalkyl, preferably C₁₀-C₁₆ fluoroalkyl, in particular    comprising 1 to 40 fluorine atoms, preferably 5 to 35 fluorine    atoms, preferably 10 to 30 fluorine atoms;-   X=alkoxy, preferably C₁-C₄ alkoxy, most preferably C₁ and/or C₂    alkoxy; and-   n=1 to 4, in particular 3.

In the case of fluorosilanes, in particular fluoroalkylsilanes, thatcomprise alkoxy groups, particularly durable coatings having excellentlong-term performance can be achieved on microstructured components orsubstrates. The coatings have excellent hydrophobicity and remain boundto the substrate or component for long periods of time, even inhigh-pressure applications.

According to another, particularly preferred embodiment of the presentinvention, for the modifier, a silane according to general formula VI

R¹ _(4-(n+m))SiR² _(m)X_(n)  (VI)

is used, where

-   R¹=alkyl, in particular C₁-C₂₀ alkyl, preferably C₈-C₁₈ alkyl,    preferably C₁₀-C₁₆ alkyl;    -   aryl, in particular C₆-C₂₀ aryl, preferably C₆-C₁₀ aryl;    -   olefin, in particular terminal olefin, preferably C₂-C₂₀ olefin,        preferably C₈-C₁₈ olefin, particularly preferably C₁₀-C₁₆        olefin;-   R²=alkyl, in particular C₁-C₃ alkyl, preferably methyl;-   X=halide, in particular chloride and/or bromide, preferably    chloride;    -   alkoxy, in particular C₁-C₆ alkoxy, particularly preferably        C₁-C₄ alkoxy, most preferably C₁ and/or C₂ alkoxy; and-   n=1 to 3, in particular 3, and-   m=0 to 2, in particular 0 or 2, preferably 0.

In this regard, particularly good results are obtained if, for themodifier, a silane according to general formula VII

R_(4-n)SiX_(n)  (VII)

is used, where

-   R=alkyl, in particular C₁-C₂₀ alkyl, preferably C₈-C₁₈ alkyl,    preferably C₁₀-C₁₆ alkyl;-   X=alkoxy, preferably C₁-C₄ alkoxy, most preferably C₁ and/or C₂    alkoxy; and-   n=1 to 4, in particular 3.

It has also proven effective if the silane comprises three reactivechemical functions and/or groups, in particular three hydrolysablechemical functions and/or groups, and is preferably a trialkoxysilane.

Within the context of the present invention, good results are alsoobtained if a silane having organic C₁-C₂₀ groups, in particular C₈-C₁₈groups, preferably C₁₀-C₁₆ groups, is used as the modifier. In thisregard, it has proven effective for the organic groups to benon-hydrolysable and to preferably be selected from alkyl, aryl andolefin groups that may be partially fluorinated or perfluorinated.

Within the context of the present invention, good results are obtainedif the silane is selected from fluoroalkyltrialkoxysilanes, the silanein particular being 1H,1H,2H,2H-tridecafluorooctyltriethoxysilane.

In addition, particularly good results are obtained if the silane is analkyltrialkoxysilane, in particular selected from the group consistingof C₁₂ alkyltrialkoxysilanes, C₁₄ alkyltrialkoxysilanes and C₁₆alkyltrialkoxysilanes and mixtures thereof.

As the applicant surprisingly found, coatings having properties that arecomparable to coatings obtained by fluorinated compounds, in particularfluoroalkylsilanes, can be achieved on the basis of organosilanes, inparticular alkylsilanes, preferably having C₁₀-C₁₆ alkyl groups,particularly preferably having C₁₂, C₁₄ or C₁₆ alkyl groups. Thecoatings according to the invention on the basis of alkylsilanes cannotbe removed from the surface of the substrate or component inhigh-pressure applications, and also produce excellent results in stresstests or “provocation tests”, in particular in terms of long-termperformance.

As regards the composition of the modification reagent and its manner ofapplication, in principle any suitable option can be used. Within thecontext of the present invention, however, it has proven effective forthe modification reagent to be used in the form of a solution and/ordispersion.

In particular when using liquid dispersions or solutions, modificationreagents can be set to have a very low content of modifiers suitable forcoating microstructured components with monolayers.

Within the context of the present invention, water and/or organicsolvents are generally used as solvents and/or dispersion media.

As regards the specific selection of solvent and/or dispersion medium,water and/or polar organic solvents can be selected as solvents and/ordispersion media. In this regard, it has proven effective for the polarorganic solvents to be selected from the group consisting of primary andsecondary alcohols, ketones, ethers, amines, amides, esters, sulphoxidesand mixtures thereof, in particular methanol, ethanol, isopropanol,dimethylether, diethylether, acetic acid ethylether, THF, DMF, DMSO andmixtures thereof, preferably ethanol and isopropanol and mixturesthereof. Within the context of the present invention, mixtures of waterand alcohols, in particular ethanol and/or isopropanol, are preferablyused.

Likewise, however, non-polar organic solvents can also be used as thesolvent and/or dispersion medium within the context of the presentinvention, in particular toluene, tetrachloromethane, chloroform,alkanes and mixtures thereof, in particular toluene, tetrachloromethane,C₅-C₉ alkanes, in particular pentane, hexane, heptane and/or octane, andmixtures thereof. Non-polar organic solvents are primarily used when thework will take place under anhydrous conditions.

The modifier can be used in any concentration that is suitable forproducing particularly thin layers, preferably monolayers, on thesubstrate or component surface. However, it has proven effective withinthe context of the present invention for the modification reagent tocontain the modifier in amounts of from 0.003 to 2 mol/l, in particularfrom 0.006 to 0.5 mol/l, preferably from 0.01 to 0.1 mol/l, preferablyfrom 0.02 to 0.05 mol/l, based on the modification reagent.

As for the duration for which the substrate or component, in particularthe substrate or component surface, is in contact with the modificationreagent, this can vary over wide ranges depending on the otherconditions. Within the context of the present invention, however, it hasbeen found that very good results can be obtained if the substrate orcomponent is brought into contact with the modification reagent for aperiod of from 5 minutes to 20 hours, in particular from 30 minutes to15 hours, preferably from 1 to 10 hours, preferably from 2 to 8 hours,particularly preferably from 4 to 7 hours.

In terms of the temperatures at which the substrate or component isbrought into contact with the modification reagent, the same applieshere in that in principle any temperature that allows the substrate orcomponent to be coated in a particularly thin, homogeneous layer issuitable. However, it has been shown that good results are obtainedusing the modifiers or modification reagents used within the context ofthe present invention if the substrate or component is brought intocontact with the modification reagent at a temperature in the range offrom 10 to 50° C., in particular from 15 to 40° C., preferably from 20to 30° C.

Within the context of the present invention, it has proven particularlyeffective for the substrate or component to be treated with ultrasoundat least intermittently, in particular at fixed intervals, while incontact with the modifier. Ultrasound treatment enables the modifier tobe exchanged within the capillaries and channels of the microstructuredcomponent, allowing for particularly uniform coatings.

According to a preferred embodiment of the present invention, themodifier is dried and/or hardened after being brought into contact withthe substrate or component, in particular after being applied to thesubstrate or component. Drying, hardening or cross-linking the modifierproduces, on the substrate or component, a layer, preferably in the formof a monolayer, that is at least substantially closed and is durably andrigidly bound to the substrate or component.

The temperature ranges within which the modifier is dried, hardened orcross-linked can vary widely depending on the modifier. However,particularly good results are achieved, in particular where silanes andsiloxanes are used as the modifier, when the modifier is dried and/orhardened at temperatures in the range of from 20 to 250° C., inparticular from 30 to 220° C., preferably from 50 to 200° C., preferablyfrom 80 to 180° C., particularly preferably from 100 to 150° C., mostpreferably from 110 to 140° C. Preferably, the modifier or the coatingobtained using the modifier is tempered within the aforementionedtemperature ranges, such that cross-linking takes place within the layerand the layer is bound to the substrate or component surface by means ofchemical bonds, in particular covalent bonds.

As for the time for which the modifier is dried and/or hardened, this islikewise highly dependent on the properties of the modifier used in eachcase. Within the context of the present invention, however, it hasproven advantageous if the modifier is dried and/or hardened for aperiod of from 0.1 to 10 hours, in particular from 0.2 to 8 hours,preferably from 0.5 to 5 hours, preferably from 0.75 to 3 hours,particularly preferably from 1 to 2 hours.

Within the context of the present invention, the excess modificationreagent can also be removed prior to or following the method step ofdrying and/or hardening. To ensure that the coated substrate orsurface-modified substrate or component subsequently functions properlyin the long-term, it has proven effective to remove excess modificationreagent or modifier not bound to the substrate or component surface.This can be done prior to the drying or hardening, for example bymechanical removal, in particular using towels or non-woven materials orcontactlessly, or following the drying or hardening, for example byrinsing using water or a solvent. Where the coated microstructuredsurface is freed from excess modification reagent or modifier using asolvent, at least one alcohol, in particular isopropanol and/or ethanol,preferably isopropanol, is usually used.

In this regard, particularly good results are obtained if excessmodification reagent is removed from the substrate or component surface,in particular from the microstructure, prior to the drying and/orhardening. This can effectively prevent the microstructure becomingclogged or its geometry changing. In particular when the microstructuredsystem is a nozzle system, large increases in homogeneity andreproducibility of the coating can be achieved. In this regard, excessmodification reagent is preferably removed mechanically, in particularcontactlessly. In this regard, contactless removal of excessmodification reagent should be understood within the context of thepresent invention to mean that the modification reagent is removed fromthe surface of the substrate or component, in particular in the regionof the microstructure, without parts of the cleaning apparatus cominginto contact with the surface being cleaned. Preferably, the excessmodification reagent is removed by means of a pressurised gas, inparticular by means of compressed air, or by the action of rotaryforces, e.g. in a spin rinse dryer.

Within the context of the present invention, it is preferable for theexcess modification reagent to be removed by means of a spin rinsedryer, i.e. under the effect of rotary forces. Particularly good resultsare obtained in this regard if the rotary forces acting on the componentare in the range of from 5 to 12 g, in particular from 6 to 11 g,preferably from 8 to 10 g, where “g” denotes acceleration due to gravityof 9.81 ms⁻².

Removing excess modification reagent by means of rotary forces, inparticular by means of a spin rinse dryer, is advantageous firstly inthat the modification reagent is reliably removed from even the finestcapillary structures of the microstructured component, and secondly inthat the removal of the modification reagent does not cause anyevaporation effects, which, for example, lead to other modifiersprecipitating out or accumulating due to concentration effects.

In this context, removing the excess modification reagent by means ofrotary forces is possible at room temperature, in particular within atemperature range of from 15 to 30° C. The excess modifier can alsousually be removed by rotary forces in normal ambient air. Moreover, itis simple to remove excess modification reagent using rotary forces evenon industrial scales.

According to a preferred embodiment of the present invention, thesurface of the substrate or component is activated before the substrateor component is brought into contact with the modification reagent. Inthis regard, it has proven advantageous for all the materials of thecomponent to be activated in one operation, i.e. in one method step.

In this case, activating the substrate or component surface should beunderstood within the context of the present invention to mean that thesubstrate or component surface is chemically or physically prepared forthe subsequent surface modification. This can be done, for example, byproducing functional reactive groups on the substrate or componentsurface that can subsequently form bonds, in particular covalentchemical bonds, with the modification reagent or modifier. Activationbeforehand generally considerably increases the quality of thesubsequent surface modification or coatings; in particular, thelong-term performance of the surface-modified substrates or componentsis significantly improved since activation ensures a considerably betterbond between the modifier and the substrate or component surface.

According to a preferred embodiment of the method according to theinvention, the method according to the invention is a method formodifying, in particular hydrophobing, surfaces of microstructuredcomponents, in particular for high-pressure applications, as describedabove, wherein

-   (a) in a first method step, the surface of a microstructured    component is activated (optionally after a previous additional    cleaning step),-   (b) in a subsequent method step, the microstructured component is    brought into contact, in particular treated, with a modification    reagent containing at least one modifier, and-   (c) in a subsequent method step, the modifier is dried and/or    hardened and/or cross-linked.

As regards the method step of activating the substrate or componentsurface, this can be carried out in many different ways. Usually,however, the substrate or component is activated chemically and/orphysically, preferably chemically. In physical activation, for example,the substrate or component surface is bombarded with particles orelectromagnetic radiation, such as in sputtering or plasma/coronatreatment. By means of the physical treatment, the surface of thesubstrates or components is cleaned and (preferably at the same time)reactive chemical groups, in particular polar reactive chemical groups,are formed on the surface of the substrate or component and allow themodifier, in particular silanes, to bond during the subsequent surfacemodification. In chemical activation, the substrate or component surfaceis chemically altered by being brought into contact, in particulartreated or transformed, with a chemical reagent such that reactivechemical groups, in particular polar reactive chemical groups, areformed on the surface of the substrate or component.

Within the context of the present invention, it has proven effective forthe substrate or component to be activated by the action of anactivation reagent, in particular an activation solution. The activationreagent or activation solution contains chemical substances that caninteract with the substrate or component surface and activate saidsurface by chemical transformation. Glass substrates or siliconsubstrates, which have a native oxide layer, are usually activated suchthat silanol groups, i.e. free hydroxy functions, that can subsequentlyreact with the modifier are formed on the surface of the glass orsilicon dioxide layer.

Generally, the substrate or component is activated under acidic and/orbasic conditions. The acids or lyes are usually Brønsted acids or bases.

Within the context of the present invention, however, it has provenadvantageous for the substrate or component to be activated underoxidising conditions, in particular under acidic and/or basic oxidisingconditions, preferably under acidic oxidising conditions. Underoxidising conditions, in particular acidic to slightly basic oxidisingconditions, the substrate or component surface is not only activated toan excellent extent. In the process, the visual properties of the glassor silicon substrates are preferably retained, which allows for simplequality control of the microstructured components using optical methods.In addition, activation under oxidising conditions significantlyincreases the silanol group density on the substrate or component.

As regards the activation reagent used within the context of the presentinvention, a multiplicity of reagents are suitable for this inprinciple. Particularly good results are obtained, however, if theactivation reagent is selected from the group consisting of acids andlyes, in particular alkaline lyes, solutions of tetramethylammoniumhydroxide, mineral acids, such as sulphuric acid, muriatic acid ornitric acid, halogenated organic acids, piranha solution, SC-1 solutions(SC-1=Standard Clean 1 according to the RCA method; RCA=RadioCorporation of America) and mixtures thereof, preferably SC-1 solutions.For further information on the RCA method, reference is made to Kern,W., Cleaning Solutions based on hydrogen peroxide for use in siliconsemiconductor technology. RCA review, 1970. 31: pp. 187-206.

According to an embodiment of the present invention, the activationreagent can be water, aqueous ammonia solution and aqueous hydrogenperoxide solution in a volume-to-volume ratio in the range of from10:1:1 to 5:2:2, preferably from 8:1:1 to 5:2:1, particularly preferablyof 5:1:1. These solutions are also referred to as SC-1 solutions andwere developed in semiconductor technology for the RCA method in orderto clean silicon wafers.

In this regard, particularly good results are obtained if the aqueousammonia solution comprises from 5 to 30 wt. % NH₃, particularlypreferably 25 wt. % NH₃, based on the ammonia solution. Equally, theaqueous hydrogen peroxide solution can comprise from 10 to 40 wt. %H₂O₂, preferably 30 wt. % H₂O₂, based on the aqueous hydrogen peroxidesolution. Activation reagents of the aforementioned type areexceptionally suitable for activating glass and silicon surfaces undermild, slightly alkaline conditions, producing almost no difficult tohandle waste substances.

According to a further embodiment of the invention, the activationsolution can comprise sulphuric acid and aqueous hydrogen peroxidesolution in a volume-to-volume ratio of from 20:1 to 1:1, in particularfrom 10:1 to 1:1, preferably from 5:1 to 1:1, preferably from 3:1 to1:1, particularly preferably of 7:3. These activation solutions areusually referred to as piranha solutions or Caro's acid.

In this respect, the sulphuric acid can be concentrated, in particularcan comprise a content of from 99.0 to 99.9 wt. % H₂SO₄, based on thesulphuric acid. Equally, the aqueous hydrogen peroxide solution cancomprise from 10 to 40 wt. % H₂O₂, particularly preferably 30 wt. %H₂O₂, based on the aqueous hydrogen peroxide solution.

In addition, the activation reagent can likewise be an alkaline lye, inparticular caustic soda. In this regard, particularly good results areobtained if the activation reagent comprises at least one alkali metalhydroxide, in particular sodium and/or potassium hydroxide, preferablysodium hydroxide, in amounts of from 5 to 25 wt. %, preferably of 20 wt.%, based on the activation reagent. Excellent activation of thesubstrate or component surface can also be achieved using theaforementioned base activation reagents. In some cases, however, inparticular when using highly alkaline activation reagents, glass and/orsilicon substrates may become discoloured, which makes visual componentchecks more difficult; for this reason, this method is less preferablewithin the context of the present invention.

As for the duration for which the substrate or component surface istreated with the activation reagent, this can vary over wide rangesdepending on the activation reagent used in each case. Within thecontext of the present invention, however, it has proven effective forthe substrate or component to be treated with the activation reagent fora period of from 0.1 to 10 hours, in particular from 0.5 to 8 hours,preferably from 1 to 5 hours. Treating the substrate or componentsurface with the activation reagent for the aforementioned periods oftime allows the substrate or component surface to be completelyactivated, without the surface of the substrate or component beingnoticeably corroded or eroded.

As for the temperatures at which the substrate or component is treatedwith the activation reagent, this can in turn vary over wide rangesdepending on the activation reagent in each case. However, it has provenadvantageous for the substrate or component to be treated with theactivation reagent at temperatures in the range of from 20 to 100° C.,in particular from 30 to 90° C., preferably from 40 to 85° C.,preferably from 50 to 80° C., particularly preferably from 60 to 75° C.Increasing the temperature slightly increases the activation rate, as aresult of which the substrate or component surface is activated veryeffectively and uniformly, even when mild activation reagents are used.

Within the context of the present invention, it is also preferable forthe activated substrate or component (in particular when the substrateor component is based on glass or elementary silicon) to be washed withwater following treatment with the activation reagent and to then bestored under water until it is brought into contact with themodification reagent. In addition, particularly good results areobtained if the activation solution is at least intermittently treatedwith ultrasound while the substrate or component surface is beingactivated by the activation reagent. Ultrasound treatment allows theactivation solution to be thoroughly mixed particularly uniformly, andin particular allows the activation reagent to be thoroughly mixed andexchanged even in any capillaries and fine channels located within thesubstrate or component.

Within the context of the present invention, the substrate or componentis usually cleaned prior to activation and/or surface modification, inparticular is degreased and/or freed of particles. Cleaning, inparticular degreasing, the substrate or component surface has provenparticularly effective when a particularly uniform coating is desired.For example, greasy residues are not always completely removed from thesubstrate or component surface by the aforementioned activation reagentspreferably used. In other words, the parts of the substrate or componentcovered with the grease or fatty acids are not accessible or onlyinsufficiently accessible for the activation, for which reason thesurface is not modified or is only poorly modified at these sites. Forthis reason, the substrate surface should be cleaned or degreased,preferably using organic solvents, before the substrate or componentsurface is treated with the activation reagent.

In this regard, it has proven effective for the substrate or componentto be cleaned by being treated with an in particular volatile organicsolvent, in particular an alcohol, preferably ethanol or isopropanol, ora non-polar aprotic solvent. In this respect, alkanes, e.g. pentane,hexane, heptane or octane, have proven particularly effective forremoving even non-polar substances from the surface of the substrate orcomponent.

According to a particular and preferred embodiment of the presentinvention, in a final method step, in particular a method step (d), thequality of the surface modification, in particular the hydrophobing, isdetermined. In this regard, it is preferable for the quality of thesurface modification to be determined for each component. A finalcomprehensive quality check on the microstructured component is alwaysbeneficial and is necessary in particular when the microstructuredcomponent is to be fitted in medical devices, e.g. inhalation devices.

As regards determining the quality of the surface modification, this canbe carried out in many different ways. Within the context of the presentinvention, however, particularly good results are obtained if thequality of the surface modification is determined using optical methods,in particular on the basis of image data. In this regard, it has proveneffective for the surface modification to be determined using opticalmethods, in particular by comparing measured parameters with targetvalues in a spatially resolved manner.

If the component consists in part of glass, preferably of glass andsilicon, the transparency to visible light can be used for aparticularly effective quality check when the material is glass. Opticalmethods can be used to check an at least partially transparentmicrostructured component in a simple automated manner since it issimple to detect deviations in the thickness of the surfacemodification, in particular of the coating, as well as clogging in themicrostructure.

Within the context of the present invention, in this regard thecomponents are usually categorised on the basis of the determination ofthe quality of the surface modification, in particular faulty componentsare discarded. In particular, a visual quality check on themicrostructured components allows microstructured components for medicalapplications to be produced on industrial scales.

According to a preferred embodiment of the present invention, thepresent invention relates to a method for modifying, in particularhydrophobing, surfaces of microstructured components having a polarsurface, in particular for high-pressure applications, a microstructuredcomponent being brought into contact, in particular treated, with amodification reagent, the surface properties of the substrate beingmodified by chemical and/or physical interaction between the componentsurface and the modification reagent, the modification reagentcomprising at least one modifier and a silane according to generalformula VI

R¹ _(4-(n+m))SiR² _(m)X_(n)  (VI)

being used for the modifier, where

-   R¹=alkyl, in particular C₁-C₂₀ alkyl, preferably C₈-C₁₈ alkyl,    preferably C₁₀-C₁₆ alkyl;    -   aryl, in particular C₆-C₂₀ aryl, preferably C₆-C₁₀ aryl;    -   olefin, in particular terminal olefin, preferably C₂-C₂₀ olefin,        preferably C₈-C₁₈ olefin, particularly preferably C₁₀-C₁₆        olefin;-   R²=alkyl, in particular C₁-C₃ alkyl, preferably methyl;-   X=halide, in particular chloride and/or bromide, preferably    chloride;    -   alkoxy, in particular C₁-C₆ alkoxy, particularly preferably        C₁-C₄ alkoxy, most preferably C₁ and/or C₂ alkoxy; and-   n=1 to 3, in particular 3, and-   m=0 to 2, in particular 0 or 2, preferably 0.

It goes without saying that further advantageous embodiments of themethod according to the invention described in connection with otherembodiments of the method according to the invention also apply mutatismutandis to this special embodiment.

According to another preferred embodiment of the present invention, thepresent invention relates to a method for modifying, in particularhydrophobing, surfaces of microstructured components having a polarsurface, in particular for high-pressure applications, a microstructuredcomponent being brought into contact, in particular treated, with amodification reagent, the surface properties of the substrate beingmodified by chemical and/or physical interaction between the componentsurface and the modification reagent, the modification reagentcomprising at least one modifier and the modifier being selected fromthe group consisting of silanes, siloxanes, polysiloxanes and/orsiliconates and mixtures thereof, the modifier being dried and/orhardened after being brought into contact with the component and excessmodification reagent being removed following the method step of dryingand/or hardening by treating the component in a spin rinse dryer.

It goes without saying that further advantageous embodiments of themethod according to the invention set out in connection with otherembodiments of the method according to the invention also apply mutatismutandis to this special embodiment.

According to a likewise preferred embodiment of the present invention,the present invention relates to a method for modifying, in particularhydrophobing, surfaces of microstructured components having a polarsurface, in particular for high-pressure applications, a microstructuredcomponent being brought into contact, in particular treated, with amodification reagent, the surface properties of the substrate beingmodified by chemical and/or physical interaction between the componentsurface and the modification reagent, the modification reagentcomprising at least one modifier and the modifier being selected fromthe group consisting of silanes, siloxanes, polysiloxanes and/orsiliconates and mixtures thereof, the quality of the surfacemodification being determined in a final method step.

It goes without saying that further advantageous embodiments of themethod according to the invention set out in connection with otherembodiments of the method according to the invention also apply mutatismutandis to this special embodiment.

According to a second aspect of the present invention, the presentinvention also relates to a microstructured component comprising asurface modification, in particular a coating, obtainable according toone of the aforementioned methods.

For further details on this aspect of the invention, reference can bemade to the above explanations on the method according to the invention,which apply mutatis mutandis to the microstructured component accordingto the invention.

According to a third aspect of the present invention, the presentinvention also relates to a microstructured component, in particular anozzle system, of a microfluidic system, comprising at least one inletopening, at least one outlet opening and inner surfaces formed bymicrostructures, the inner surfaces being modified, in particularcoated, at least in part.

The microstructured component according to the invention is preferably anozzle body used in SMI-type inhalers. Particularly preferably, thecomponent according to the invention is a DJI nozzle.

According to a preferred embodiment of the present invention, the outersurface of the component is also modified, in particular coated, inparticular in the region of the outlet opening. It is preferable to coatnot only the inner surfaces of the microstructured component accordingto the invention, but also to coat at least some regions of the outersurface, at least in the region of the outlet opening(s), since coatingat least the region of the outlet opening(s) prevents particles frombeing deposited in this region and thus effectively counteracts thenozzles being clogged or blocked.

Within the context of the present invention, particularly good resultsare obtained if the surface of the component is in particular at leastsubstantially modified, in particular coated. Therefore, it ispreferable within the context of the present invention for the entiresurface of the component to be in particular at least substantiallymodified, in particular coated.

It has proven particularly effective for the surface of the component tobe modified so as to be rendered hydrophobic, in particular to behydrophobed. When using hydrophilic substrates specifically, e.g. glassor silicon substrates, the surface properties can be adjusted in atargeted manner by hydrophobing.

Generally, the surface of the component is modified by transformationusing a modification reagent.

As regards the modification reagent, this can be selected from allsuitable reagents. Within the context of the present invention, however,particularly good results are obtained if the modification reagentcontains at least one silane, one siloxane, one polysiloxane and/or onesiliconate. For further details on the preferred modification reagents,reference can be made to the above explanations regarding the methodaccording to the invention.

According to a preferred embodiment of the present invention, themicrostructured component comprises two outlet openings. In this regard,the component can in particular comprise channels that open into theoutlet opening(s).

It is also common for the channels to directly or indirectly connect theinlet openings and the outlet openings. An indirect connection betweenthe inlet opening and outlet opening by means of the channels should beunderstood to mean that there are additional parts of the microstructureprovided between the inlet and outlet openings, such that the channelsconnect the individual regions or parts of the microstructure.

According to a preferred embodiment of the present invention, thechannels of the outlet openings are oriented towards one another at anangle of from 50 to 130°, in particular from 60 to 120°, preferably from70 to 110°, preferably from 80 to 100°, particularly preferably from 85to 95°, most preferably at 90°. Preferably, the channels are orientedsuch that their linear extensions intersect and form the aforementionedangles. Since the channels are oriented towards one another, fluidsexiting the outlet nozzles under pressure collide with one another at aslight distance from the microstructured component and are atomised bythe impact. An impact disc is formed made of finely distributed aerosolhaving low kinetic energy, which allows pharmaceutical activeingredients to reach deep into the lungs.

Within the context of the present invention, the component generallycomprises a filter region preferably arranged between the inlet openingand the outlet opening. By means of the filter region, fine impuritiescontained in the fluid intended to exit through the outlet openings, inparticular through the nozzles, are retained. Impurities of this kindcan, for example, be produced by the fluid reacting with the walls ofthe fluid storage tank. In addition, it is also possible for solids toprecipitate out over time while the fluid is being stored.

Within the context of the present invention, the microstructures, inparticular the channels, can also have a depth and/or diameter in therange of from 0.1 to 50 μm, in particular from 0.5 to 40 μm, preferablyfrom 1 to 20 μm, preferably from 2 to 15 μm, particularly preferablyfrom 2.5 to 10 μm, most preferably from 3 to 8 μm. The microstructuredepth should be understood to be the height difference between themicrostructure and the surrounding component surface in the case ofouter surface structures. The depth of the microstructures can, forexample, be precisely adjusted by material-removing methods, such asmilling, drilling, laser cutting or, in the case of silicon wafers,etching.

According to a particular embodiment of the present invention (not setout in more detail), outer surfaces of the component are alsomicrostructured in particular at least in part, in particular in theregion of the outlet openings. Microstructuring in the region of theoutlet openings makes it possible to again effectively counteractparticle adhesion, thereby preventing the outlet opening(s) frombecoming blocked or clogged.

Within the context of the present invention, the component usuallyconsists of at least two different materials, in particular glass andsilicon.

Furthermore, the different materials can in particular be at leastsubstantially square, in particular plate-like. Having the materials ina square or plate-like shape means the two materials can be connected ina particularly solid durable lasting manner since large surfaces can beinterconnected.

It is also preferable for the different materials to be rigidlyinterconnected, in particular bonded.

Within the context of the present invention, particularly good resultsare obtained if at least one of the different materials ismicrostructured, preferably on its surface. As explained above,microstructures can be obtained within a component that comprises morethan one material by at least one of the materials comprising amicrostructure in one of its surfaces. By connecting the two materials,an inner surface of the composite material can be produced from theouter surface of one material.

According to a preferred embodiment of the present invention, themicrostructure is obtained within the component by connecting thedifferent materials.

For further details on this aspect of the invention, reference can bemade to the above explanations on the other aspects of the invention,which apply mutatis mutandis to the microstructured component accordingto the invention.

Lastly, according to a fourth aspect of the present invention, thepresent invention relates to a discharge apparatus, in particular anatomiser, for fluids, in particular for medical liquids, preferablyliquid medicinal products, comprising at least one microstructuredcomponent as described above.

Within the context of the present invention, the discharge apparatusgenerally comprises at least one liquid medicinal product.

The medicinal products present in the discharge apparatus or emittedthereby are usually dispersions, suspensions or solutions of at leastone pharmaceutical active ingredient.

In this regard, the pharmaceutical active ingredient can be selectedfrom the group consisting of corticosteroids and/or(para)sympathomimetics.

Particularly good results are obtained within the context of the presentinvention if the pharmaceutical active ingredient is selected from thegroup consisting of terbutalin, salbutamol, trospium, in particulartrospium chloride, flutropium, in particular flutropium bromide,tiotropium, in particular tiotropium bromide, oxitropium, in particularoxitropium bromide, ipratropium, in particular ipratropium bromide,fenoterol, budesonide, fluticasone, in particular fluticasonepropionate, glycopyrronium, in particular glycopyrronium bromide,ciclesonide and beclometasone, in particular beclometasone propionate,and the physiologically compatible salts and derivatives thereof.

As regards the concentration of the pharmaceutical active ingredient inthe solution or dispersion, this can of course vary over wide ranges.However, particularly good results are obtained if the solution ordispersion contains the active ingredient in amounts of from 0.01 to 100mmol/l, in particular 0.05 to 80 mmol/l, preferably from 0.1 to 50mmol/l, preferably from 0.5 to 20 mmol/l, particularly preferably from0.6 to 10 mmol/l, most preferably from 0.8 to 5 mmol/l, based on thesolution or dispersion. Within the above concentration ranges, thecompositions can be discharged from the device and atomised particularlyeffectively, undesirable precipitation of substances also beingeffectively prevented in particular.

The solvent or dispersion medium can be selected from allphysiologically compatible solvents or dispersion media. Usually, thesolvent or dispersion medium is selected from the group consisting oforganic solvents, in particular alcohols, preferably ethanol orisopropanol, preferably ethanol, and water, and mixtures thereof.

Within the context of the present invention, formulations comprisingsolvents or dispersion media consisting of ethanol and water andmixtures thereof are given particular consideration; preferably,mixtures of water and ethanol in the range of from 1:80 to 1:100,particularly preferably of 1:90, are selected. In principle, however,the volume-to-volume ratios of water to ethanol in the mixtures used assolvents or dispersion media can vary over wide ranges. In particular interms of the particle size and particle size distribution in the aerosolobtained, suitable results can also be expected in view of the presenttests for mixtures in which the volume-to-volume ratio of water toethanol in the mixtures varies in the range of from 10:1 to 1:50, inparticular from 5:1 to 1:30, preferably from 2:1 to 1:20, preferablyfrom 1:1 to 1:15, particularly preferably 1:2 to 1:10.

In addition, it has proven effective if the solution or dispersion has apH in the range of from 2 to 8, in particular from 2.2 to 7, preferablyfrom 2.5 to 6.5, preferably from 2.8 to 6. Within the context of thepresent invention, it is possible to store solutions and dispersions ofmedicinal products in the acidic pH range with long-term stability andto discharge them without blocking or clogging the nozzles.

Within the context of the present invention, it is preferable for themedicinal product to be an aqueous or aqueous-ethanolic solution ordispersion of budesonide.

According to a preferred embodiment of the present invention, themedicinal product is a combination of

-   (a) at least one active ingredient A selected from the group    consisting of budesonide, fluticasone, ciclesonide and    beclometasone, preferably ciclesonide, and the physiologically    compatible salts and derivatives thereof, and-   (b) at least one active ingredient B selected from the group    consisting of-   6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one;-   6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-acetic acid ethyl    ester)-1,1-dimethylethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one;-   6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-acetic    acid)-1,1-dimethylethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one;-   8-{2-[1,1-dimethyl-2-(2,4,6-trimethylphenyl)-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;-   6-hydroxy-8-{1-hydroxy-2-[2-(4-hydroxy-phenyl)-1,1-dimethylethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one;-   6-hydroxy-8-{1-hydroxy-2-[2-(4-isopropyl-phenyl)-1,1-dimethylethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one;-   8-{2-[2-(4-ethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;-   8-{2-[2-(4-fluoro-3-methyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;-   8-{2-[2-(4-fluoro-2-methyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;-   8-{2-[2-(2,4-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;-   8-{2-[2-(3,5-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;-   8-{2-[2-(4-ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;-   8-{2-[2-(3,5-dimethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;-   4-(4-{2-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-2-methyl-propyl}-phenoxy)-butyric    acid;-   8-{2-[2-(3,4-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;-   8-{2-[2-(2-chloro-4-fluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;-   8-{2-[2-(4-chloro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;-   8-{2-[2-(4-bromo-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;-   8-{2-[2-(4-fluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;-   8-{2-[2-(4-fluoro-3-methoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;-   8-{2-[2-(4-fluoro-2,6-dimethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;-   8-{2-[2-(4-chloro-2-methyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;-   8-{2-[2-(4-chloro-3-fluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;-   8-{2-[2-(4-chloro-2-fluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;-   8-{2-[2-(3-chloro-4-fluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;-   8-{2-[2-(2,6-difluoro-4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;-   8-{2-[2-(2,5-difluoro-4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;-   8-{2-[2-(4-fluoro-3,5-dimethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;-   8-{2-[2-(3,5-dichloro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;-   8-{2-[2-(4-chloro-3-methyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;-   8-{2-[2-(3,4,5-trifluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;-   8-{2-[2-(3-methyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;    and-   8-{2-[2-(3,4-dichloro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,    and the physiologically compatible salts and derivatives thereof.

According to another preferred embodiment of the present invention, themedicinal product is a combination of

-   (a) at least one active ingredient A, as described above,-   (b) at least one active ingredient B, as described above, and-   (c) at least one active ingredient C selected from the group    consisting of trospium, in particular trospium chloride, flutropium,    in particular flutropium bromide, tiotropium, in particular    tiotropium bromide, oxitropium, in particular oxitropium bromide,    ipratropium, in particular ipratropium bromide, glycopyrronium, in    particular glycopyrronium bromide, and the physiologically    compatible salts and derivatives thereof.

For further active ingredient combinations that are preferable withinthe context of the present invention, reference is made to WO2008/020056 A1 and WO 2008/020057 A1.

For further details on this aspect of the invention, reference can bemade to the above explanations on the other aspects of the invention,which apply mutatis mutandis to the discharge apparatus according to theinvention.

Lastly, according to a fifth aspect of the present invention, thepresent invention also relates to a method for assessing the surfacemodification of a microstructured component, a provocation solutionbeing repeatedly conducted through the microstructured component, inparticular under high pressure, and the flow behaviour of theprovocation solution being observed as it exits the microstructuredcomponent.

According to a preferred embodiment of the present invention, thequality of the surface modification, in particular the suitability ofthe modification reagent for the surface modification, is determined bythe flow behaviour over time, in particular the change in the flowbehaviour over time, of the provocation solution as it exits themicrostructured component.

It has been surprisingly shown that suitable provocation solutions canin a targeted manner produce deposits in the microstructure of themicrostructured component that alter the flow behaviour of the solutionwithin the component and in particular as it exits the outlet openings,specifically over very short periods of time. When the microstructuredcomponent is used in practice, for example in inhalation devices, thesedisruptions to the flow behaviour do not occur.

The results from the provocation tests can be used to define improvedmicrostructures, in particular nozzle geometries, and for example totest coating reagents for their suitability for surface modification. Asa result, the use of a microstructured component and the dischargeapparatus can be extended to include new fields of application and newmaterials.

In addition, the provocation tests can also be used to identifymicrostructured components having better long-term performance. In thecase of modification reagents in particular, there must be asufficiently large safety margin between the conditions under which thecoating no longer fulfils its purpose and the usage conditions, so that,in particular in medical inhalation devices, the user is always reliablygiven the therapeutic dose of medicinal products.

Within the context of the present invention, a provocation solutionshould be understood to be a solution or dispersion by which changes tothe flow behaviour in microstructured components can be caused underconditions that are far removed from the actual conditions under whichthe microstructured component is used. For example, the provocationsolutions can contain reactive chemical substances or particles that canlead to the microstructures becoming clogged or the flow conditionswithin the microstructured component being altered.

Preferably, the provocation solution is conducted through themicrostructure from 10 to 1,000 times, preferably from 15 to 500 times,preferably from 25 to 250 times.

Within the context of the present invention, the flow behaviour of theprovocation solution as it exits the microstructured component can bedetermined by optical, in particular photographic, methods. In thisregard, it is possible in particular to photograph the exit of theprovocation solution from the outlet openings and categorise the imagedata by comparing it with a catalogue compiled beforehand. Inparticular, this method makes it possible to study the change in theflow behaviour over time.

According to a preferred embodiment of the present invention, themicrostructured component is a nozzle body, in particular a DJI nozzle.

Within the context of the present invention, the provocation solution isusually aqueous and/or alcohol-based, in particular is a water-ethanolmixture. In this regard, it has proven effective for the provocationsolution to have a volume-to-volume ratio of alcohol to water in therange of from 1:1 to 20:1, in particular from 3:1 to 15:1, preferablyfrom 6:1 to 12:1, preferably of 9:1.

In this regard, the provocation solution can also have a pH of at most4, in particular of at most 3, preferably of at most 2. Likewise,however, good results can also be obtained if the provocation solutionhas a pH in the range of from 0 to 4, in particular from 0.1 to 3,preferably from 1 to 2.

According to a particular embodiment of the present invention, theprovocation solution comprises at least one additional substanceselected from silicic acids and organic chemical compounds, inparticular active ingredients.

Where the provocation solution comprises organic chemical compounds, ithas proven effective for the provocation solution to comprise theorganic chemical compound, in particular the active ingredient, inamounts of from 0.01 to 5 mmol/l, in particular from 0.1 to 3 mmol/l,preferably from 0.5 to 2 mmol/l, preferably of 1 mmol/l, based on theprovocation solution.

To determine the suitability of coatings or to assess their durability,a multiplicity of active ingredients can be used. In the experimentscarried out to date, it has been noted that fenoterol, for example,provides particularly convincing results.

Likewise, however, the provocation solution can also comprise silicicacid in amounts of from 0.001 to 2 wt. %, in particular from 0.01 to 1wt. %, preferably from 0.05 to 0.5 wt. %, preferably of 0.1 wt. %, basedon the provocation solution.

For further details on this aspect of the invention, reference can bemade to the above explanations on the other aspects of the invention,which apply mutatis mutandis to the method according to the inventionfor assessing the surface modification of a microstructured component.

The individual features of the present invention can be usedindependently of one another or combined.

Additional advantages, features, properties and aspects of the presentinvention are set out in the claims, the embodiments and the followingdescription given on the basis of the drawings, in which:

FIG. 1 is a schematic view of a microstructured component showing anillustration of the microstructure including the outlet openings and thechannels leading to the outlet openings,

FIG. 2 shows a cut-out of the microstructured component shown in FIG. 1,in which the region of the microstructured component around the outletopenings is shown in detail and the coating is visible,

FIG. 3 is a schematic section through a discharge apparatus, inparticular an atomiser, in the non-tensioned state,

FIG. 4 is a schematic section through the discharge apparatus, inparticular the atomiser, from FIG. 1 in the tensioned state, rotatedthrough 90° compared with FIG. 3,

FIG. 5 shows an example group I spray pattern (image in two differentperspectives) for the tested inhalers comprising a DJI nozzle,

FIG. 6 shows an example group II spray pattern (image in two differentperspectives) for the tested inhalers comprising a DJI nozzle,

FIG. 7 shows the change over time in group III spray patterns forinhalers comprising a DJI nozzle that has uncoated nozzle bodies,according to pH,

FIG. 8 shows the 10-day average rate of group III spray patterns forinhalers comprising a DJI nozzle that has uncoated nozzle bodies,according to pH,

FIG. 9 shows the change over time in group I spray patterns for inhalerscomprising a DJI nozzle that has coated nozzle bodies, according to themodifier,

FIG. 10 shows the change over time in group II spray patterns forinhalers comprising a DJI nozzle that has coated nozzle bodies,according to the modifier,

FIG. 11 shows the change over time in group III spray patterns forinhalers comprising a DJI nozzle that has coated nozzle bodies,according to the modifier,

FIG. 12 shows the 10-day average rate of group III spray patterns forinhalers comprising a DJI nozzle that has coated nozzle bodies,according to the modifier,

FIG. 13 shows the change over time during long-duration tests in group Ispray patterns for inhalers comprising a DJI nozzle that has nozzlebodies coated with 1H,1H,2H,2H-tridecafluorooctyltriethoxysilane(F1308-OET) compared with inhalers having uncoated nozzle bodies,

FIG. 14 shows the change over time during long-duration tests in groupII spray patterns for inhalers having a DJI nozzle that has nozzlebodies coated with 1H,1H,2H,2H-tridecafluorooctyltriethoxysilane(F1308-OET) compared with inhalers having uncoated nozzle bodies,

FIG. 15 shows the change over time during long-duration tests in groupIII spray patterns for inhalers having a DJI nozzle that has nozzlebodies coated with 1H,1H,2H,2H-tridecafluorooctyltriethoxysilane(F1308-OET) compared with inhalers having uncoated nozzle bodies,

FIG. 16 shows the 10-day average during long-duration tests of group IIIspray patterns for inhalers having a DJI nozzle that has nozzle bodiescoated with 1H,1H,2H,2H-tridecafluorooctyltriethoxysilane (F1308-OET)compared with inhalers having uncoated nozzle bodies,

FIG. 17 shows the change over time in group I spray patterns forinhalers having a DJI nozzle that has coated nozzle bodies, for othermodifiers,

FIG. 18 shows the change over time in group II spray patterns forinhalers having a DJI nozzle that has coated nozzle bodies, for othermodifiers,

FIG. 19 shows the change over time in group III spray patterns forinhalers having a DJI nozzle that has coated nozzle bodies, for othermodifiers,

FIG. 20 shows the 10-day average rate of group III spray patterns forinhalers having a DJI nozzle that has coated nozzle bodies, for othermodifiers,

FIG. 21 shows the yield of category I nozzle bodies depending on theselected modifier.

In the drawings, the same reference numerals are used for like orsimilar parts, matching or similar properties and advantages beingobtained even is the description is not repeated.

FIG. 1 is a schematic view of a microstructured component 1 according tothe invention, in particular a nozzle body. The illustration in FIG. 1shows the microstructure of a nozzle body comprising a DJI-type nozzle,as preferably used in an SMI-type inhaler. The nozzle body is preferablya microfluidic sandwich system and consists of a square microstructuredsilicon chip that is bonded to a 0.5 mm thick, preferably very smoothglass plate (e.g. a glass produced using the “float” method, preferablybased on borosilicate).

The microstructured component 1 consists of two rigidly interconnectedplate-like materials, preferably a silicon wafer and a glass wafer. Thecomponent 1 has inlet openings 2 and outlet openings 3 for receiving ordischarging preferably pressurised fluids, preferably liquids. Channels4 that are preferably oriented towards one another adjoin the outletopenings. The channels 4 and outlet openings 3 have either a round ornon-round shape, in particular preferably an angular cross section of adiameter or depth of from 2 to 10 μm and a width of from 5 to 15 μm, inparticular a depth of from 4.5 to 6.5 μm and a width of from 7 to 9 μm.

The microstructures in the silicon chip are preferably produced usingetching techniques. The etching depth on the silicon chip can varydepending on the solvent or dispersion medium or method used.Preferably, the depth is 5.6 μm for nozzle bodies intended for atomisingaqueous formulations, or 7.0 μm for those intended for atomisingethanolic formulations, as determined by the different physico-chemicalproperties of the solutions or dispersions. The overall cross-sectionalsurface area of the outlet openings 3 is usually from 30 to 500 μm, across section range of from 30 to 200 μm being preferred. The outletchannels 4 preferably have a length of 40 μm and a width of 8 μm.

In a component 1 having at least two outlet openings 3, the jetdirections can be inclined relative to one another at an angle of from50 to 130°; preferably, an angle of from 70 to 110°, from 85 to 95°, ormost preferably of 90°, is obtained. The outlet openings 3 are generallyspaced apart by 10 to 200 μm, in particular by 10 to 100 μm, preferablyby 30 to 70 μm. Preferably, the spacing between the outlet openings 3 is50 μm. The jet directions meet one another close to the nozzle openings(preferably at a distance of less than 1 mm, preferably of less than 100μm, from the surface of the nozzle body) and the fluid is atomised bythe liquid jets colliding.

In the following, a preferred embodiment will be described in which themicrostructures defined by the inlet openings 2, the outlet openings 3and the channels 4 are made in the surface of a silicon wafer. Themicrostructures can be made in the silicon wafer by any suitable method;however, the microstructuring is preferably made by etching methods, asknown for example from semiconductor technology. To create surfaceswithin the microstructured component 1 that are suitable for receivingand subsequently dispensing pressurised fluids, the microstructures aremade in one of the materials, preferably the silicon wafer, of thecomponent and connected to the second component, preferably a glasswafer. In this way, cavities in the form of microstructures can beobtained in the microstructured component.

A fine filter 5 consisting of a multiplicity of filter channels can bearranged between the outlet openings 3 or channels 4. The passages orfilter channels in the filter structure within the fine filter 5 areselected such that, as far as possible, even the smallest of impuritiescannot enter the region of the outlet openings, i.e. the nozzle region,and clog them or change the geometry. The diameter of the filterchannels or filter passages is usually from 0.5 to 20 μm, preferablyfrom 2 to 5 μm. The fine filter 5 usually has a zigzag arrangement toincrease the surface area. Particles that are larger than the crosssections of the filter channels can be retained in the fine filter 5 toprevent the outlet channels becoming clogged. The filter channels in thefilters of the fine filter 5 are formed by protrusions that arepreferably arranged in a zigzag shape so as to increase the filtersurface area. For example, at least two rows of protrusions form azigzag configuration. A plurality of rows of protrusions can also beformed, the rows preferably abutting one another at acute angles andforming the zigzag configuration. In embodiments such as this, the inletand outlet can comprise an inflow region for unfiltered fluid and anoutflow region for filtered fluid, respectively, the inflow region andoutflow region being substantially exactly as wide as the filter 5 andsubstantially as high as the protrusions for the inlet and outlet sidesof the filter 5. The zigzag configuration formed by at least two rows ofprotrusions preferably has a tilt angle of from 20 to 250°. Furtherdetails on this component design can be found in WO 94/07607 A1.

The microstructured component 1 can comprise an outflow region or aplenary chamber 6. In particular, the plenary chamber 6 is arrangedbetween the outlet openings 3 or channels 4 and the fine filter 5. Theplenary chamber can comprise column structures 7 depending on theapplication. By means of the column structures 7 in the plenary chamber6, a multiplicity of channels are produced and preferably run into thechannels 4 of the outlet openings 3.

The microstructured component 1 or nozzle body forms a rigid systemdesigned to make two liquid jets impact against one another once theyexit the outlet openings 3. When the impact is correct, an impact discforms, at the boundary of which the fine aerosol is produced. Thecritical parameters for aerosol formation include, inter alia, the flowrate (around 100 m/s) and the angle of impact. Material deposited in thenozzle channels can thus noticeably affect the aerosol formation, forexample by deflecting the jet, and cause “spray anomalies”, which couldeven prevent the spray cloud from appearing due to jet divergency.

The surfaces of the microstructured component 1 have a coating 8 whichdetermines the surface properties of the microstructured component. Inthis regard, both the inner and outer surfaces of the microstructuredcomponent 1 can be coated. Preferably, at least the inner surfaces ofthe microstructured component are coated in order to prevent particlesadhering thereto and to thus prevent the nozzle becoming blocked orclogged.

According to a preferred embodiment of the present invention, the outersurface of the component 1 is also modified or coated at least in theregion of the outlet openings.

FIGS. 3 and 4 are schematic views of a discharge apparatus according tothe invention in the form of a manually operated medical device. Thedischarge apparatus according to FIGS. 3 and 4 is preferably apropellant-free atomiser 9 that discharges predetermined amounts of aliquid or a liquid medicinal formulation as a preferably respirable orinhalable aerosol 11 per actuation cycle. Aerosol droplets having anaerodynamic diameter of from 0.5 to 5 μm can be inhaled by a user. Theaverage aerodynamic droplet size of the aerosol 11 is preferably withina diameter range of from 0.5 to 10 μm, in particular in the range offrom 0.5 to 5 μm.

For the atomisation, a suitable nozzle in the form of themicrostructured component 1 according to the invention is used. Whenoperating the atomiser 9, a distinction is drawn between the“non-tensioned state”, where the metering volume in the pressure chamber12 is empty (FIG. 3), and the “tensioned state”, where the pressurechamber 12 is full (FIG. 4). When the atomiser 9 is tensioned, the upperhousing part 13 is rotated by a fixed angle of rotation, e.g. 180°,relative to the inner housing part 14 and the lower housing part 15. Bymeans of an internal screw thread mechanism, the relative rotationdrives a plunger pump such that a predetermined, optionally adjustableamount of liquid 10 is conveyed out of the container 16 into thepressure chamber 12 while the mainspring 17 of the pressure generator 18is tensioned at the same time (the final state of the tensioning processis shown in FIG. 4). When the atomiser 9 is triggered, i.e. when alocking ring 19 is actuated by means of a button 20, the energy from thepressure generator 18 stored in the mainspring 17 is released. Thetubular piston 21 used previously to convey the liquid then pushes intothe pressure chamber 12 while the return valve 22 is closed, such thatthe amount of liquid predetermined by the stroke movement of the tubularpiston 21 is discharged from said chamber through the outlet opening 3.The apparatus is now back in the non-tensioned state, as shown in FIG.3.

In the embodiment shown, by means of the container 16, the tubularpiston 21 is rigidly connected, e.g. integrally moulded, glued orsnapped on, to a mount 23 belonging to the pressure generator 18. Thecontainer 16 is secured, in particular clamped or latched, in theatomiser 9 by means of the mount 23 such that the tubular piston 21enters the fluid chamber of the container 16 and/or is in fluidcommunication with the liquid 10 in the container 16 and said liquid canbe sucked up via the tubular piston. The container can optionally bereplaceable. For this purpose, the device housing can be designed suchthat it can be opened or partly removed (e.g. in the form of a cap-likelower housing part as disclosed in WO 07/123381 A1).

The container 16 used in the atomiser 9, which is equipped with a doseindicator or meter 24, is designed for removing a plurality of dosageunits. For this purpose, the container has to be designed such that theinternal pressure remains substantially the same, even during liquidremoval, to ensure the same amount of liquid 10 is always removed duringsuction. For this purpose, it is possible in principle to use both acontainer 16 that comprise a rigid container wall, the internal pressureof which is kept constant by means of ventilation and which is in turndescribed for example in WO 06/136426 A1, and a container 16 having aflexible wall that is slid into the container interior at least in partwhen liquid is removed in such a way that the reduction in the internalvolume keeps the internal pressure constant.

Containers 16 in which the flexible wall is formed by a substantiallydeformable, collapsible and/or contractable pouch are preferred in thiscase. Various embodiments of containers of this kind are described indocuments WO 00/49988 A2, WO 01/076849 A1, WO 99/43571 A1, WO 09/115200A1 and WO 09/103510 A1. Particularly preferably, the container 16consists of a flexible multi-layer film pouch that is closed at thebottom and is directly connected in its upper region to a supportingflange, preferably made of plastics material, a container cap weldedthereon for connecting to the mount 23 of the atomiser 9, an outerprotective sleeve and a top seal (for details see WO 99/43571 A1 and WO09/115200 A1). The typical filling volume of a container 16 consists offrom 3.0 to 3.6 ml of inhalation solution.

A filter system 25 upstream of the microstructured component 1 can belocated in the liquid outlet region of the pressure chamber 12. Thisfilter system 25 preferably consists of a plurality of filter componentsthat are arranged one behind the other and differ from one another inparticular on account of the filter technology used. The filterthresholds of the individual filter components are of such a level thateach filter lets through smaller particles than the one behind it inaccordance with the largest exchange principle. By combining differentfilter techniques and arranging filters to have a gradually increasingdegree of separation or gradually decreasing pore sizes, it is possibleto achieve a high filter capacity, i.e. the precipitation of relativelylarge amounts of particles without the filter becoming blocked, andthorough filtering. In addition to collecting solid particles of aparticular size, the filter can optionally collect additional materialvia adsorption. For this purpose, filters of different structures anddifferent materials can be used, such that the adsorption properties aredifferent from filter to filter. Accordingly, combining differentfilters makes it possible to catch even more particles and in particularparticles that can deform under pressure owing to the various adsorptioneffects. For further details on preferred filter systems, reference ismade in particular to WO 2012/007315.

The entire system consisting of the pressure generator 18, having themainspring 17, and the microstructured component 1 is preferablyconstructed such that, when the spray mist is produced, not only arerespirable droplet sizes formed, but also the spray mist cloud itselfremains there for enough time to allow the patient to adapt theirinhalation thereto in a simple manner. Preferably, spray times are from0.5 to 2 s, in particular from 1 to 2 s. The pressure at which thefluid, in particular the liquid drug, leaves the outlet openings is from50 to 1,000 bar, in particular from 200 to 600 bar.

Depending on the size of the components and the liquid formulation to beatomised, the aerosol 11 contains a distinctively high fine particlefraction (in this case: the fraction of the spray made up by particleshaving diameters of 5 μm) of for example 50%, preferably 65%,particularly preferably of 80%, in particular for ethanolicformulations, and the spray cloud produced is preferably slower than inother portable inhalers, e.g. MDI-type inhalers. This leads tosignificantly higher deposition in the lungs than in other conventionalinhalers, such as pMDIs or DPIs. In addition, the atomiser 9 accordingto the invention is distinguished by a remarkably long duration ofspray, which enables good patient coordination in terms of themtriggering the atomiser 9 or inhaler.

Depending on the required daily dosage and the intended period ofapplication, the atomiser 9 can be designed to dispense from 10 to 200,in particular from 20 to 150, preferably from 60 to 130 sprays. A slideon the meter 24 indicates how many strokes have been consumed or howmany are left. After the specific stroke number is reached, thedischarge apparatus preferably locks itself automatically and is blockedfrom being used further. A “tail-off”, as can be noted in meteringaerosols that use compressed air, is thus prevented.

To prepare the atomiser 9 for application, a container 16, in particularin the form of a cartridge, must first be inserted. For this purpose,the lower housing part 15 has to be removed. After the container hasbeen inserted, the removed lower housing part 15 is placed back on andthe device is primed by being actuated a number of times (=dischargingthe air from the system). Only after this time is the atomiser 9 readyfor operation and can guarantee constant dispensing of a dosage.

The aim of the priming is to completely fill the metering chamber orpressure chamber 12. When the device is actuated while the mouthpiece isoriented vertically upwards, the lower housing part 15 is rotatedtowards the upper housing part 18 by 180° until the audible clicking andlatching. In the process, the mainspring 17 is tensioned, the button 20springs forwards when latching is complete and indicates that theatomiser 9 is in the tensioned state by sitting flush with the sides.Pressing the button 20 generates the aerosol; the position of theatomiser 9 can be freely selected.

EMBODIMENTS

1. Methods Used and Experiment Set-Up

For the following tests, the surfaces of planar substrates made ofsilicon and glass, and a microstructured nozzle system were modified andtheir properties studied. Commercially available glass planar substratesproduced from borosilicate glass using the “float” method were primarilyused as planar substrates for the tests described below. Nozzle bodieshaving microstructures according to the drawing in FIG. 1 were used asthe microstructured nozzle system.

Si/glass planar substrates consist of the same materials as the nozzlebodies and are cut to size from the nozzle body starting materials, i.e.a glass wafer (borosilicate glass having a smooth surface according tothe “float” method) and a silicon wafer (111). Their size is that of aconventional microscope slide (26 mm×75 mm) and they are used as areference material since the nozzle body used is difficult to access formany characterisation tests.

The nozzle body used for the following tests is a microfluidic sandwichsystem, consisting of a 2.05×2.55 mm² microstructured silicon chipbonded to a 0.5 mm-thick glass plate (in this case a borosilicate glassproduced using the “float” method). The internal microstructure of thenozzle body used consists of an inlet region having an inlet opening, azigzagged fine filter, a columnar microstructure 7 and the front nozzleregion. The etching depth on the silicon chip is 7.0 μm. The distancebetween the two outlet openings 3 is 50 μm.

During the triggering, a liquid solution or dispersion flows through theinlet region into the microstructure under very high pressure. In thezigzagged fine filter, the fine filter structures having an openingwidth of 3 μm retain relatively large particles to prevent the outletchannels becoming clogged by such relatively large particles. The outletchannels have a length of 40 μm and a width of 8 μm. The inhalationsolution leaves the nozzle body through the two front nozzle outletchannels. The aerosol is generated outside the nozzle body by the twoliquid jets produced impacting against one another.

The structure of the nozzle body forms a rigid system that ensures thetwo liquid jets impact against one another correctly. After havingexited the nozzle channels, the two liquid jets collide at an angle of90° to each other. When the impact is correct, an impact disc forms, atthe boundary surface of which the fine aerosol is produced. The criticalparameters for aerosol formation include the flow rate (around 100 m/s)and the angle of impact.

As part of the tests described here, when fitted the functioning of thesurface-modified nozzle bodies is checked on the basis of SMI atomisersas designed according to FIGS. 3 and 4.

1.1. Preparing Surface-Functionalised Nozzle Bodies and Si/Glass PlanarSubstrates by Means of Solution Coating

The coating process begins by activating the silicon or glass surfaces.The activation cleans the surface of adherent dirt and increases thenumber of free reactive silanol groups on the surface by means ofoxidation. The reactive silanol groups on the surface are capable ofreacting with functional silanes. Tests were carried out on modificationreagents based on various chloroalkylsilanes and alkylalkoxysilanes,which form a robust siloxane scaffold on the surface following thereaction.

The quality of the surface coating on Si/glass planar substrates isdetermined by means of contact angle measurement and layer thicknessmeasurement using spectroscopic ellipsometry. For the microstructure ornozzle body, the capillary action test can be carried out.

1.1.1 Preparing the Nozzle Body Sample

The nozzle bodies are functionalised in PEEK trays. PEEK (polyetherether ketone) is a very inert material and is exceptionally suitable forthis application. Nozzle bodies have to be functionalised in traysbecause the very small nozzle bodies would otherwise not be able to behandled in the process tanks. The tray has a reaction chamber that hasspace for around 50 to 75 nozzle bodies and can be closed by means of alid. In addition, an agitator that ensures the chamber is thoroughlymixed can be positioned below the reaction chamber. Both the lid and thereaction chamber are provided with small pores, such that solution canflow through the chamber.

Before coating, the nozzle bodies are transported into the reactionchamber by means of a vacuum cup. Since the nozzle bodies have alreadybeen cleaned, no special cleaning steps have to be carried out on thecomponent, as is the case for silicon or glass planar substrates.

1.1.2 Preparing the Planar Substrate Samples

The silicon and glass planar substrates do not undergo the cleaningsteps like the nozzle bodies, so they have to be thoroughly cleanedagain using water and isopropanol prior to being activated. Thesubstrates are cut to the conventional slide dimensions and are alsocoated in an inert tray having space for around 20 substrates. The Sisubstrates must have been stripped as close to the functionalisation aspossible, i.e. should undergo an HF treatment; this ensures a uniformSiO₂ film on the surface. When the silicon substrates are stripped, thenatural oxide layer on the surface is removed. After this removal, theoxide film regrows slowly and generates a uniform thin oxide film.

For the stripping, a 6% hydrogen fluoride solution is used, in which thesilicon substrates should remain for at least 20 minutes. Following theremoval therefrom, the Si substrates are thoroughly rinsed with waterand sorted into the substrate trays for coating.

The glass substrates used have a fire-polished side and an extra-smoothside produced in the float method. To improve the reproducibility of themeasurement results in the tests described here, the fire-polished sideof the glass substrates was marked using a diamond scriber before thestart of the process. This is the side on which the ellipsometricmeasurements will be taken later in the process.

1.1.3 Overview of the Surface Functionalisation Process Steps

The process begins by cleaning the surfaces of adherent dirt. Next, thecleaned surface is oxidatively activated. After a rinsing step in whichthe activation solution is washed off the nozzle bodies or substrates,the actual coating process can begin. If the coating is carried iscarried out using an alkyltrialkoxysilane, the coating reagent has to betransformed into the active silanol component by means of precursorsplitting. After coating, the samples are dried and then dried in anoven at 120° C.

1.1.3.1 Cleaning and Activating Nozzle Bodies and Si/Glass PlanarSubstrates

The coating process usually begins by cleaning and activating thesilicon or glass surfaces. The samples are cleaned and activated in oneoperation. The following cleaning and activation solutions are used fornozzle bodies and Si/glass planar substrates in the following tests.

1.1.3.1.1 NaOH Solution (Highly Alkaline Activation)

The samples are added to 25% caustic soda and stirred. Next, they arethoroughly rinsed with lots of water. In most cases, the method worksvery well, but relatively often leads to clouding on the glass orsilicon surface since the surface has already been etched (glasscorrosion). In the following, therefore, this method is only used forpreliminary tests since clouding on the nozzle body is unacceptable dueto the visual quality control.

1.1.3.1.2 RCA Solution (RCA=Radio Corporation of America)

The next activation solution, referred to as RCA solution, is StandardClean 1 solution (SC-1 solution), which was developed for the RCA methodin order to clean silicon wafers. The samples are added to a solution ofH₂O:NH₃ (aq. 25%):H₂O₂ (aq. 30%) in a volume-to-volume ratio of 5:1:1 at70° C. and stirred. The Si/glass substrates are stirred constantly for20 minutes, whereas nozzle bodies are treated for one hour alternatingbetween treatment with ultrasound (20 minutes each time) and stirring(10 minutes each time). Next, the substrates or nozzle bodies arethoroughly rinsed with water. The substrates or nozzle bodies are storedin water until the start of the process.

1.1.3.1.3 Piranha Solution (Acidic Oxidative Activation)

The samples are added to a solution of H₂SO₄ (conc.):H₂O₂ (aq. 30%) in avolume-to-volume ratio of 7:3 at 70° C. and stirred. The Si/glasssubstrates are stirred constantly for 20 minutes, whereas nozzle bodiesare treated for one hour alternating between treatment with ultrasonicwaves (20 minutes each time) and stirring (10 minutes each time). Next,the samples are thoroughly rinsed with water and can be stored in wateruntil coating.

1.1.3.2 Surface Functionalisation of Silicon and Glass Surfaces UsingAlkyltrialkoxysilanes

The trialkoxysilanes are added to an alcoholic solution and, since theyare a precursor compound, have to first be proteolytically split intothe active silanol components. By way of example, this reaction can betaken from equation 1 below. The silanol compound is usually producedwithin five hours, as indicated in equation 1 for the example1H,1H,2H,2H-tridecafluorooctyltriethoxysilane (example substance used:Dynasylan® F8261 from Evonik) from the starting compound.

The active silanol components now associate with the activated surfaceand bond covalently following tempering.

During the functionalisation, the solution is stirred constantly. Unlikethe substrates, nozzle bodies are treated with ultrasound at fixedintervals during the functionalisation. Following functionalisation, thesamples are removed from the solution and dried for one hour in air.After drying, the samples are tempered in an oven for 1 hour at 120° C.Following tempering, the substrates are carefully rinsed using a smallamount of isopropanol. Nozzle bodies can also be used without anyadditional cleaning step.

1.1.3.2.1 Surface Coating Process Using Alkyltrialkoxysilanes in anIsopropanol-Water Mixture

1.1.3.2.1.1Hydrolysis of Starting Compound

A 0.1-1.0 vol. % solution of the silane is added to an acidicalcohol-water mixture (2-propanol/H₂O/HCl_(conc) 89.8:10:0.2) andstirred at room temperature for at least five hours.

The compound can be used after five hours and must be used up within 24hours.

1.1.3.2.1.1 Surface Functionalisation

The samples are added to the functionalisation solution and constantlystirred during coating. Nozzle bodies are repeatedly treated withultrasound at fixed intervals during the coating. Afterfunctionalisation, the samples are removed from the liquid, and the trayfor the substrates and the tray for the nozzle bodies are passed to acellulose cloth for drying. The samples are dried for one hour in air.

1.1.3.2.1.2 Condensation

The samples are tempered in an oven at 120° C. Next, the substrates arecarefully washed using isopropanol. Nozzle bodies can also be used aftertempering without any additional cleaning step. The finished nozzlebodies and substrates can be stored under laboratory conditions.

1.1.3.3 Surface Functionalisation of Silicon and Glass Surfaces Using

Chloroalkylsilanes Surface functionalisation by means ofchloroalkylsilanes is based on the condensation reaction between thefree silanol group on the surface and the chlorine function of thefunctional alkylsilane.

Chlorosilanes are very sensitive to moisture and their reactions must becarried out in dry, non-polar solvents such as toluene,tetrachloromethane or alkanes such as hexane.

1.1.3.3.1 Schematic Surface Coating Process Using Alkylchlorosilanes inToluene

The surface of substrates and nozzle bodies are activated as describedabove.

1.1.3.3.1.1 Drying the Solvent

The toluene is dried for at least 12 hours using a molecular sieve (type4 A). The ratio is 10 g molecular sieve to 1 litre solvent.

1.1.3.3.1.2 Surface Functionalisation

The samples are coated in 0.07 to 0.7 mol solutions of the chlorosilanewhile being stirred constantly. Nozzle bodies are repeatedly treatedwith ultrasound at fixed intervals during the coating. Afterfunctionalisation, the samples are removed from the liquid, and the trayfor the substrates and the tray for the nozzle bodies are passed to acellulose cloth for drying. The samples are dried for one hour in air.

1.1.3.3.1.3 Condensation

After drying, the samples are tempered in an oven at 120° C. Next, thesubstrates are carefully washed using isopropanol. Nozzle bodies canalso be used after tempering without any additional cleaning step. Thefinished nozzle bodies and substrates can be stored under laboratoryconditions.

1.2 Categorising Nozzle Bodies after Coating

The coated nozzle bodies are divided into the following nozzlecategories I to IV.

Category I

The nozzle region, the zigzagged filter and the support structure of thenozzle body are as free of residues as possible.

Category II

The nozzle region is free of residues, yet there are some in thezigzagged filter and column structure.

Category III

One nozzle channel contains residues or is completely clogged.

Category IV

Two nozzle channels contain residues or are completely blocked.

1.3. Provocation of Nozzle Blockages in the Nozzle Body

1.3.1 Provocation Solutions

Provocation solutions are intended to cause the phenomenon of nozzleblockage or the jet divergency effect as often as possible. Therefore,in terms of their parameters, they are selected such that they willcause a very high number of clogged nozzles during a test. This isnecessary in order to cause a sufficient number of clogged nozzle usingas few samples as possible to allow meaningful assessments to be made asto whether a modification influences the occurrence of clogged nozzles.

1.3.2 Provocation of Nozzle Blockages During in-Use Operation of anAtomiser Having a DJI Nozzle (=Provocation Tests)

1.3.2.1 the Phenomenon of Nozzle Blockages

In an SMI inhaler having a DJI nozzle, the aerosol production is basedon two microfluidic jets impacting against one another. These jets aregenerated in the nozzle body by two rectangular nozzle outlet channelsthat are oriented at a 90° angle to one another. For the sprayperformance, it is critical that the two liquid jets impact against eachother correctly. Provoked particle deposits in one or both nozzlechannels can disrupt the proper impact by deflecting the jets and canlead to changes in the spray pattern and deviations in the fine particlefraction. In this document, the term “jet divergency” should beunderstood to mean group III spray patterns, which have an altered fineparticle fraction or in which at best only a small portion of the amountof liquid to be discharged by atomiser actuation is actually dischargedas an aerosol. A more comprehensive definition of the term is asfollows: The phenomenon of jet divergency (jet deflection due to nozzleblockage) is a reversible or permanent, partial or totalblockage/clogging of one or both nozzle channels of the nozzle body thathas been caused by particles in the inhalation solution and leads tosprays having a different fine particle fraction.

1.3.2.2 Allocating Spray Patterns in Provocation Tests

Provocation tests allow various factors influencing the phenomenon ofnozzle blockage to be assessed. The test is designed such as to block asmany inhaler nozzles as possible over the duration of the test. For thispurpose, the atomisers are triggered once a day and the spray pattern isdetermined visually. This type of test scenario is referred below as an“in-use test” since it reproduces the daily use of an atomiser by auser, at least in relation to frequency of use.

The spray pattern (SP) of the atomiser is recorded over the entireduration of the test in accordance with the categorisation set out aboveand is then evaluated. For this, the individual spray patterns aresummarised in the three following superordinate groups: Normal (“good”)sprays (group I), spray pattern anomalies (group II) and sprays havingan altered fine particle fraction (group III=jet divergency). The effectof a test parameter on the incidence can be deduced from comparing itwith a reference.

FIG. 5 shows example group I spray patterns. Sprays of this kind have adominant, undivided spray cloud (with at most just a small amount ofside spray). Normally, the spray cloud is symmetrical.

FIG. 6 shows example group II spray patterns. The spray patterns in thisgroup show split spray clouds. FIG. 6 shows a spray cloud splitsymmetrically, although asymmetrically split spray clouds or sprayssplit multiple times also belong to this spray pattern group. It shouldbe noted here that detecting the division of the spray cloud may dependon the perspective of the observer. In (automatic) spray cloud imagedetection, therefore, use is preferably made of two cameras that arearranged at a 90° angle to the aerosol cloud axis and take the images ofthe aerosol cloud from two different perspectives at the same time asthe device is triggered.

Group III spray images, for which the fine particle fraction isconsiderably different from or less than the group I and II sprays (dueto the impaired aerosol formation), cannot be detected using simpleimage recording systems. However, when special illumination is provided,the liquid exiting the nozzle, e.g. in one or two very thin jets, can bedetected visually. In the spray patterns for this group, the liquid jetsdo not impact against each other due to them being deflected (and so thespray cloud typical of DJI nozzles is not formed). Therefore, jetdivergency has occurred.

1.3.2.3 Spray Pattern Assessment

The spray patterns are assessed visually (in a series of tests carriedout manually) or by means of camera technology (in series of testscarried out using a stroke robot) and are assessed upon each stroke ofthe device. The spray pattern detected on the test day is recordedtogether with the stroke number. In the evaluation, the recorded spraypatterns are assigned to the individual groups and the progression ofthe spray pattern over time is observed.

During a provocation test, the atomiser is mounted in the laboratory atconstant temperature and atmospheric humidity. The spray patterns areassessed for all the devices within a test on the same day.

Devices put into operation for the first time have to be primed beforethe start of the test.

To subsequently assess the spray patterns, the primed device is liftedinto a suction apparatus at an angle of 45°. The distance from thesuction machine is around 20-30 cm to allow the aerosol cloud to beclearly visible. The contrast can be increased by using black cardboardas a base and a cold light source. The spray patterns are classifiedaccording to the aforementioned groups.

The spray patterns can also be assessed in an automated manner using astroke robot. For this purpose, the robot is fitted with the pre-primedatomiser and a robot arm then coordinates the tensioning and release ofthe inhaler. Two CCD cameras are oriented at a 90° angle to the aerosolcloud axis and take images of the aerosol cloud at the same time as whenthe apparatus is triggered. The spray patterns are assessed manually byan employee on the basis of the images recorded.

1.3.3 Test Set-Up for a Standard Provocation Test

The standard test set-up for a provocation test is as follows:

Number of inhalers: 30-150 (depending on the influencing parametersbeing tested)

In-use mode: 1×1 (1 stroke/day) or 1×2 (2 strokes/day)

Test point: Spray pattern (specification according to spray patterncatalogue)

Duration of test: 28-120 days; similar to 1-month/4-month patient usage

Formulation: Ethanol/water 90/10 (v/v), pH 2.0

Number of references: 30-75

1.3.3.1 10-Day Average and Provocation Reference

The individual spray pattern curves in a provocation test can be subjectto large fluctuations over the duration of the test. The number ofdevices having clogged nozzles is time-dependent and increases linearlyafter some time, often then reaching a steady state around which thesystem spreads. Therefore, it is not always possible to determine aprecise, final rate. For this reason, in addition to the spray patterncurves, the average rate of group III sprays is determined for each testbranch over the last ten days of the test (i.e. the 10-day average rateis determined). The actual scale of the influence of one test parameteron the incidence in group III sprays can only be discovered by comparingit with an internal provocation reference. In this respect, aprovocation reference is a group of inhalers that are missing thefeature being studied, e.g. nozzle coating. They represent the originalstate of the device and thus make it possible to draw meaningfulconclusions on any modification.

1.4. Instrumental Analytics

1.4.1 Contact Angle Measurement

The quality of the coating on Si/glass planar substrates can bedescribed on the basis of static contact angle measurement. The resultsgive information on the presence and homogeneity of the coating. Thecontact angle measurements were taken using a commercially availablemeasuring instrument (in this case a DSA 10 MKR from Krûss GmbH) havingassociated control technology and control software (evaluation accordingto the Young-Laplace model).

1.4.1.1 Bases

To assess the extent to which a liquid can wet a surface, the contactangle can be used. The contact angle is formed and measured on thesolid/liquid/gas phase contact line between the solid and liquid. Inthis regard, the extent to which a liquid can wet a surface depends onthe surface tension ratios between the solid and liquid (γ_(f/fl)),solid and air (σ_(f/g)), and liquid and air (σ_(fl/g)). The boundarysurface tensions at the droplet are in an equilibrium that can beexpressed by Young equation 2.

σ_(f/g)=γ_(f/fl)+σ_(fl/g)×cos θ  (2)

The smaller the contact angle, the better the wetting. A contact angleof 0° is referred to as total wetting; in turn, a contact angle of 180°denotes no wetting. The equilibrium described by the Young equation isadjusted according to time and temperature.

1.4.1.2 Static Vs. Dynamic Contact Angle Measurement

Unlike dynamic contact angle measurement, in static contact anglemeasurement the contact surface between the solid and liquid is notchanged during the measurement. On an ideal, chemically andtopologically homogeneous solid surface, a pure liquid in a saturatedvapour phase would have an identical dynamic and static contact angle.This state is described in the Young equation. However, the contactangle can vary according to time and location. This phenomenon iscounteracted by always measuring the contact angle immediately after theplacement of the droplet.

1.4.1.3 Description of Contact Angle Measurement

Before each measurement, the coated silicon or glass substrates arefreed of adherent dust by means of oil-free air and placed on the samplestage for the measurement. For this purpose, the silicon substrates arepositioned with the matte side downwards. By means of an automatedmicrolitre syringe, a droplet having a volume of 8 μl is placed on thesubstrate and measured immediately using the control software or controlprogram. For all contact angle measurements, double deionised waterand/or n-dodecane is used. All contact angle values stated in thedocument are average values produced generally from the measurement offive droplets. In the process, each droplet is fitted and measured tentimes by the control program similarly to the Young-Laplace model.Generally, each coating is carried out using 3-5 substrates, eachsubstrate also being used for contact angle measurement.

1.4.2 Testing Metering Behaviour Using Delivered Mass (DM) and MeteredMass (MM)

The metered dispensing of formulation by an atomiser, i.e. the measuredmass of formulation (hereinafter “metered mass” (MM)), is determined bythe structural dimensions of the inhaler and the density of theformulation solution. This is the mass of the formulation solutionreleased through the atomiser when it is actuated. The MM is determinedgravimetrically.

Generally, a small portion of the measured mass remains on the nozzle asa residue following triggering. This cannot be completely preventedsince there is always a backscattering region in the atomisationprinciple used based on an impact disc formed by two liquid jets.Therefore, the mass actually emitted from the device as a spray cloud(hereinafter “delivered mass” (DM)) is usually smaller than the meteredmass (MM). The DM is also determined gravimetrically.

1.4.3 Ellipsometry

1.4.3.1 Apparatus Set-Up

Ellipsometry is a measurement method that was used as early as in the19th century. Some of the essential components of an ellipsometer havebeen available for a very long time, whilst other components of modernellipsometers have only been developed recently.

In spectroscopic ellipsometry (SE), a white light source having amonochromator enables the ellipsometric measurements at differentwavelengths. In the process, the monochromator can be positionedupstream of the polariser or downstream of the analyser. There are alsospectroscopic ellipsometers having a rotating compensator (cf. Irene, E.A. and H. G. Tompkins, Handbook of Ellipsometry, 2005: William AndrewPub).

The ellipsometric measurements in this document were taken using aspectroscopic ellipsometer having a rotating compensator. Moreinformation on the devices used can be found in Table 1.

TABLE 1 Device used in the ellipsometry. Ellipsometer Alpha-SE ® havinga rotating compensator from J. A. Woollam Co., Inc. (USA) Spectral range390-900 nm Angle of incidence 65°, 70° and 75°, and transmission at 90°Control software Complete EASE from J. A. Woollam Co., Inc. (USA)

1.4.3.2 Description of the Ellipsometric Measurements

Before each measurement, the silicon or glass substrates are first freedof adherent dust using oil-free air. Next, the substrates are carefullyplaced on the sample stage of the ellipsometer using wafer tweezers.Care should be taken to ensure the silicon substrates are positionedwith their matte side downwards. In transparent glass substrates(Borofloat® 33, Nexterion), Scotch tape is stuck to the “tin side”before the substrates are positioned on the sample stage. Theaforementioned marking scratched into the glass before the coatingprocess using a diamond scriber should be identified.

The “tin side” is stuck down for two reasons. Firstly, rear-sidereflections on the transparent glass substrate should be prevented, andsecondly, the layer thickness should not be measured on the “float side”of the glass due to the tin residues and because it makes analysis morecomplicated. The glass used is a float glass, which is poured onto a tinbath during its production, resulting in high levels of tincontamination for a glass side.

After positioning the planar substrates on the sample stage, the stagevacuum can be switched on (better orientation parallel to the plane) andthe measurement carried out. Measurements are taken at the angles 65°,70° and 75°. After the measurement, the raw data is analysed using thecorresponding method for silicon or glass by means of the analysisfunction in the Complete EASE software.

1.4.3.3 Development of an Analysis Method for Layer ThicknessMeasurement on Silicon and Glass Planar Substrates

1.4.3.3.1 Analysis Model for Silicon Substrates

For the elliptometric measurement of the layer thickness on siliconsubstrates, the following layer model is assumed: Siliconsubstrate/native oxide/self-assembled monolayer.

On its surface, silicon forms a native oxide layer; this formsrelatively quickly, even after the HF stripping. During the coating, theself-assembled monolayer of the reactive silane compound orients itselfon this oxide layer.

This layer model can be modelled using the software (Complete EASE) onthe measurement instrument used, provided that the necessary opticalconstants and layer thicknesses are present. The optical constants forpure silicon and for the native oxide layer are known and are stored inthe analysis software database. The optical constants for the SAMs to begenerated (when present) are found in the literature or have to bedetermined by the laboratory itself. To determine the layer thickness ofthe self-assembled monolayer, the Cauchy dispersion equation in theanalysis software is used. This equation describes the refractive indexn as a function of wavelength A and is suitable for analysingultra-thin, transparent, non-absorbent films. The layer thickness of thenative oxide layer after RCA treatment was determined by experiment, theaim being a maximum of 1.5 nm.

The test is set-up as follows:

Substrate: two silicon planar substrates per test condition

HF treatment: 20 minutes prior to RCA treatment

RCA treatment [min]: 0, 5, 10, 20, 60, 90

In the standard coating method, the RCA cleaning runs for 60-90 minutes.To measure the layer thickness of the SAMs on Si substrates, therefore,a silicon oxide layer of 1.5 nm has to be used.

It is important to characterise the layer thickness of the native oxidelayer in order to later determine the layer thickness of theself-assembled monolayer on Si substrates.

1.4.3.3.2 Analysis Model for Glass Substrates

To measure the layer thickness on glass substrates, the following layermodel is assumed: Glass substrate/self-assembled monolayer.

The model does not have an oxide layer, as is the case for siliconsubstrates. It is assumed that the self-assembled monolayer bondsdirectly to the glass substrate. In addition to the specific opticalconstants for the glass used in this case, consideration was also givento how the glass behaves after RCA treatment and the material constantswere adjusted accordingly. The glass was input into the software as amaterial along with its constants such that, when the SAM refractionindex is known, the layer thickness can also be determined in this casein accordance with the Cauchy dispersion equation.

1.4.4 Capillary Action Test on Nozzle Bodies

Since the interior of the microstructure is difficult to access foranalytical methods, the evidence of whether a nozzle body is coated isgathered from a capillary action test. The test is based on a capillarybeing spontaneously filled with solvents of different polarities(generally water). The capillary action test makes it possible to checkwhether a coating is present in just a few seconds. As a polar liquid,water wets the nozzle body surface of an uncoated nozzle body andimmediately penetrates the microstructure upon contact with the nozzlebody as a result of positive capillary forces (capillary ascensioneffect). This effect can be tracked under a microscope and does notoccur, for example, if a nozzle body is coated to be hydrophobic.

If the hydrophobic coating is successful, the capillary ascension effectdoes not take place and “capillary depression” is noted. In the case ofcapillary depression, the cohesion forces between the molecules aregreater than the forces of adhesion to the surface. The liquid becomesglobular and the surface is not wetted. A liquid that does not wet thecapillary surface is expelled from the capillaries when it enters them.

1.4.4.1 Carrying Out the Capillary Action Test

Using PTFE tweezers, a coated nozzle body is oriented under themicroscope such that the internal microstructure is clearly visible.Next, a cotton bud (Q-tip) soaked in test liquid is carefully movedclose to the intake region of the nozzle body. When the Q-tip comes intocontact with the intake structure, the microstructure is not filled witha polar liquid, e.g. water, if the nozzle body is hydrophobed. As apositive check in this case, the test can be repeated using a non-polarsubstance, e.g. n-dodecane. Here, the filling is successful due to goodwetting. In this case, a nozzle body coated with a perfluorinatedalkylsilane should in turn be filled with a perfluorinated test liquid,e.g. perfluorooctane.

2. Results

2.1 Parameters Influencing the Spray Performance of Uncoated NozzleBodies

When determining a suitable provocation solution, the extent to whichdifferent external influences, in particular pH, affect the sprayperformance of the atomisers under consideration was investigatedbeforehand. In this respect, for example ethanolic formulations (90/10)of various acidity levels (pH 2.0, 2.4, 2.8, 3.2, 3.5, 5.0) were testedfor their likelihood to cause nozzle blockages.

As an example from these preliminary tests, FIG. 7 shows how the jetdivergency rate is dependent on the pH of the provocation solution. Ascan be seen in FIG. 7, pHs 2.0 and 2.4 saw an early, sharp increase ingroup III sprays. At the end of the test, a value of almost 70% wasachieved for pH 2.0 and a value of around 50% for pH 2.4. The two curvesshow the first group III sprays very early on from day 2. This iscontrary to the spray pattern curves for pHs 3.5 and 5.0, in which theproportion is almost 0% at the end of the test. It is not until day 21that a small number of individual group III sprays occur.

It is very clear from the spray pattern curves that the frequency of agroup III spray increases sharply as the pH decreases (from 5.0 to 2.0).

FIG. 8 shows the 10-day average rate (in tests over 28 days) of groupIII sprays (jet divergency) at the end of the test. As the pH increases,the number of group III sprays decreases. Therefore, the pH of theinhalation solution has a significant proportion of blocked/cloggednozzles. The lower the pH of the inhalation solution in the range testedhere, the more frequent the deviations from a group I spray (“goodspray”).

Overall, a suitable provocation solution was determined from thepreliminary investigations: Ethanol/water solution in a volume-to-volumeratio of 90:10, made acidic using HCl at pH of 2.0 (no active ingredientadded).

2.2 Functionalisation of Planar Substrates and Nozzle Bodies

2.2.1 Functionalisation of Silicon and Glass Substrates

2.2.1.1 Impact of Activation

To determine a suitable coating process for simultaneously coatingsilicon and glass, various influencing factors have to be investigated.The actual activation of the silicon and glass surfaces plays a key rolein this respect since it specifically ensures sufficient stability ofthe coating.

In one test, the effect of different activations on the properties ofthe resultant coating was investigated. Silicon and glass planarsubstrates were coated simultaneously under the same conditions usingthe four different activation methods (piranha solution, RCA solutionand NaOH solution). They were then functionalised using1H,1H,2H,2H-tridecafluorooctyltriethoxysilane (c=0.003 mol/l). Suitable1H,1H,2H,2H-tridecafluorooctyltriethoxysilane is sold, for example, byEvonik under the name Dynasylan® F8216. After coating, the substrateswere washed using 2-propanol and the static water contact angle was thenmeasured. The aim was to obtain a set of parameters for each activationthat can be used to obtain water contact angles for each activationsolution of more than 100° after coating. A water contact angle of morethan 100° indicates a homogeneous, all-over coating and goodhydrophobicity.

It was found that all the activations tested could be used tosuccessfully coat silicon/glass planar substrates and to obtain contactangles of more than 100°.

However, it was also found that the NaOH activation method was onlysuitable for the coating process to a limited extent since it frequentlycauses clouding on the glass. This phenomenon is also known as glasscorrosion. For this reason, the NaOH activation was intended forpreliminary tests only, not for the subsequent tests on the nozzle body.For the quality check on the DJI nozzles produced, it is desirable toalways be able to view the nozzles under a microscope. If the glasscomponent of the nozzle body were cloudy, this would no longer bepossible.

2.2.1.1 Effect of Coating Reagent Concentration

The impact of the coating concentration on the water contact angle onsilicon/glass planar substrates was analysed. For this purpose, thesilicon/glass planar substrates were coated with a short-chainalkylalkoxysilane (methyltrimethoxysilane=MTMS). To analyse the effectof the coating concentration, the concentration was gradually increased.Then, the substrates were characterised using static water contact anglemeasurement.

The silicon and glass planar substrates were coated in a similar mannerto the description according to section 1.1. They were activated usingan RCA activation for 20 minutes at 75° C. The substrates were coatedfor two hours without ultrasound at room temperature using thefunctionalisation reagent methyltrimethoxysilane (abcr GmbH, Karlsruhe,Germany) at various substance concentrations from 0.7 mmol/l to 70mmol/l. Next, the substrates were dried for one hour at room temperatureand lastly tempered in an oven for one hour at 120° C. The test resultsare shown in Tables 2 and 3 below.

TABLE 2 Water contact angle (with standard deviation d) of glass planarsubstrates coated with MTMS according to MTMS concentration MTMSconcentration Contact angle d [mmol/l] [°] [°] 0.7 67.11 12.45 3.5 87.456.03 7 78.32 4.47 14 83.60 8.13 35 97.39 8.46 70 103.22 2.68

TABLE 3 Water contact angle (with standard deviation d) of siliconplanar substrates coated with MTMS according to MTMS concentration MTMSconcentration Contact angle d [mmol/l] [°] [°] 0.7 51.79 7.18 3.5 79.8212.61 7 79.00 3.66 14 79.50 4.45 35 105.13 9.13 70 112.26 7.23

It was found that the water contact angle increases on both glass andsilicon as the MTMS concentration increases. At the same time,increasing the concentration at low concentrations has a somewhatgreater effect than at higher concentrations. The system approaches amaximum in the range of from 110-120°. Therefore, the contact angle isaffected less and less by further increasing the coating concentration.Overall, it can also be seen that, from a concentration of around 7mmol/l, values showing a moderate spread can be detected. In general,this points to a more homogeneous surface covering with coatingmolecules.

The data shows that it is possible to successfully coat both substratematerials in one coating process.

As is clear, the contact angle increases as the concentration of thecoating reagent increases, asymptotically approaching an apparentmaximum at higher concentrations. This seems plausible since the surfaceis saturated after a certain point, i.e. the layer has formed all overthe surface. This effect can be easily derived from the results forsilicon and glass. In the low coating concentration ranges, a greatereffect in terms of the contact angle is achieved when the concentrationis increased slightly, whereas this effect becomes weaker and weaker inthe higher concentration ranges. In this respect, doubling theconcentration from 35 mmol/l to 70 mmol/l only increases the watercontact angle by another 10°. There are no discernible generaldifferences for silicon or glass (the related requirement for coatingglass and silicon at the same time is thus met).

On the basis of the results, an optimum minimum coating concentrationfor the process can also be derived. An optimum minimum coatingconcentration should be more than 30 mmol/l since it has been found thatreliable and reproducible coatings are obtained above thisconcentration.

2.2.2 Functionalisation of Nozzle Bodies

Nozzle bodies are generally functionalised according to the procedureunder section 1.1. The external appearance of nozzle bodies aftercoating was tested.

2.2.2.1 Impact of Activation Solution

In one test, nozzle bodies were activated using the various activationsolutions and then coated with1H,1H,2H,2H-tridecafluorooctyltriethoxysilane. Next, the bodies werevisually checked for noticeable problems under a light microscope. Ingeneral, RCA-activated and piranha-activated nozzle bodies have asimilar appearance.

Generally, coated nozzle bodies have a similar surface to uncoatednozzle bodies, even under the scanning electron microscope, and are thusconsidered optically identical. A monomolecular layer of an alkylsilanecannot be directly detected by scanning electron microscopes, so coatedand uncoated nozzle bodies cannot be directly distinguished either. Allcoated nozzle bodies showed positive results in the capillary actiontest and were thus successfully coated. Morphological artefacts onlyoccurred during the surface functionalisation in very few cases. Theseartefacts only occur in a very small number of cases, so the coatingdoes not usually alter the surface morphology of the nozzles.

2.2.2.2 Capillary Action Test on Coated Nozzle Bodies

Table 4 illustrates the results of the capillary action test on tenhydrophobed, perfluorinated nozzle bodies coated with 0.03 mol/l1H,1H,2H,2H-tridecafluorooctyltriethoxysilane. The method followed thedescription in section 1.1 and was carried out after each coating usingrandomly selected nozzle body samples.

TABLE 4 Capillary action test on coated, perfluorinated nozzle bodies (N= 10) Coated Uncoated (perfluorinated) nozzle body nozzle bodySolution/formula spontaneously spontaneously (property) filled filledWater/H₂O Yes No (hydrophilic) Perfluorooctane/C8F18 No Yes(hydrophobic, oleophobic)

Direct evidence of the coating in the coated nozzle bodies is difficultto obtain since it can only be deduced by means of complicated,time-consuming measurement methods such as TOF-SIMS and ESCA aftersplitting the sandwich system. This is due to the low sample volumesresulting from the thin layer thickness of just a few nanometres.

The simplest way, therefore, is to use indirect evidence of the coatingby making use of the altered capillary effect of the microstructure. Themethod is an identity test for the presence of the coating. This test isalso suitable for large-scale quality control.

2.2.2.3 Impact on Spray Performance from Functionalisation SolutionResidues in Nozzle Bodies

In the laboratory situations used here, not all the samples emergedclean from the coating process. To be able to analyse the effect ofcoating residues on the spray pattern performance, a catalogue of faultimages having images of characteristic nozzle faults was compiled. Inthe process, the nozzles were allocated to a relevant nozzle categorydepending on the location of the residue.

2.2.2.4 Effect of the Nozzle Body Category on Spray Performance

To investigate the effect of the nozzle body category on the sprayperformance of the atomisers, nozzles coated for the long-durationprovocation test (cf. 0) were analysed under a microscope and assignedto the appropriate nozzle body category. Table 5 shows the results ofthe microscopic analysis of three batches (A to C), which were producedfor the long-duration provocation test sampling. Overall, 151 nozzlebodies were coated with 0.03 mol/l1H,1H,2H,2H-tridecafluorooctyltriethoxysilane in three different batchesand then analysed under the microscope.

TABLE 5 Results of the nozzle body categorising based on samples forlong-duration provocation test from 0 Batch Category I Category IICategory III Category IV Total A 26 (53%) 3 (6%) 14 (29%) 6 (12%) 49 B28 (54%) 0 13 (25%) 11 (21%) 52 C 21 (42%) 1 (2%) 13 (26%) 15 (30%) 50Average 49.64% 2.71% 26.52% 21.13% 151 SD  6.62% 3.12%  1.84%  8.88%

For the long-duration provocation test, 60 atomisers having coatednozzles were provided. The original nozzles were removed from thesedevices and coated nozzles were fitted. The distribution of the coatednozzles used here in relation to the nozzle body categories can be seenin Table 6.

TABLE 6 Distribution of sample nozzle body categorisation forlong-duration provocation test Category I Category II Category IIICategory IV Total 30 0 15 15 60

All the coated nozzles were fitted in provided atomisers in a traceablemanner so that it was always known which nozzle category was fitted inwhich device. They were fitted in particle-free conditions, as can beproduced under laboratory conditions. After the provocation test, theprogression of the spray patterns of the samples was analysed in a largehistogram analysis.

After 120 test days in 1×2 in-use mode, i.e. two successive strokes perday, all the 14400 sprays dispensed in the test from the 60 coatednozzles were analysed in a comprehensive histogram analysis. It wasfound that initially individual group II spray patterns were formed. Asthe test continued, clear rows or bands emerged, which indicated thatblocked devices preferably again displayed a group II spray in thefollowing strokes. As the test time progressed, group III spraysdeveloped from the group II sprays, and these would become permanentlater in the test. In this test, the absolute number of group III sprayswas relatively low, so the group II sprays were used for the bar chartanalysis. Group II sprays are a precursor for group III sprays, meaningthat they can be legitimately used for the further analysis.

It was shown that category III and category IV nozzle bodies cause groupII sprays more often than nozzle body categories I and II—15% for nozzlebody categories I and II and between 25 and 30% for nozzle bodycategories III and IV.

It was found that clean category I and II nozzle bodies have a lowernumber of spray pattern anomalies over the entire duration of the testthan category III and IV nozzles. Residues in the nozzle region thusgenerally lead to more spray pattern anomalies. The number is evengreater when both nozzle channels (category IV) are affected bydeposits. The majority of the spray pattern anomalies in this test occurlater on in the test. Category I and II nozzles always have better sprayperformance, even when broken down according to time interval. Both theshort-term and long-term spray performance of clean category I and IInozzle bodies are considerably better than that of category III and IVnozzle bodies.

Therefore, it can be concluded that the residues impair the coating orthe formation of the coating on the surface and spray performancedeteriorates.

A RAMAN spectroscopic analysis revealed that the residues are polymerresidues of the coating solution. During the drying phase afterfunctionalisation, the coating solution presumably coalesced at thesmall cavities of the microstructure and polymerised out at these pointsduring the tempering.

The results reveal that the yield of category I nozzles should be ashigh as possible for large-scale processes. For this purpose, it isappropriate to use systems that expel the excess coating solution, inparticular systems based on the use of rotary forces, e.g. SRD systems(spin rinse dryers).

2.2.3 Performance of Functional Alkylsilane Coatings in in-Use Methods(Provocation Tests)

In the following, using a standard test method, the surfacefunctionalisation of the nozzle bodies a coating method will besufficiently analysed and evaluated as a measure for preventing the riskof nozzle blockage.

2.2.3.2 Provocation Test Using Functionalised Nozzles: Performance ofthe Surface Functionalisation in Relation to Plaque Deposits Using aprovocation test (use of the predetermined provocation solution inatomisers), the behaviour of different layer functionalities whenprovoked plaque deposits occur was tested. In the process, nozzle bodieswere coated with different coating reagents according to the methoddescribed in section 1.1 (with RCA activation).

The provocation test is set up as follows:

Coating Reagents:

-   -   Dynasylan® F8261        (=1H,1H,2H,2H-tridecafluorooctyltriethoxysilane) (F1308-OET)    -   n-octyltriethoxysilane (C8-OET)    -   1H,1H,2H,2H-perfluorooctyldimethylchlorosilane (F13C8-Cl)    -   n-octyldimethylchlorosilane (C8-Cl)

Concentration: 0.03 mol/l in each case

Formulation: as in 1.3.3

Number of inhalers: 50 for each coating, 30 for reference

In-use mode: 1×1 stroke/day

Duration of test: 28 days

Test parameters: Spray pattern according to spray pattern catalogue

The basic test set-up makes it possible to compare a large number ofaspects within the experiment. Firstly, both fluorinated andnon-fluorinated alkylsilanes are used here, and secondly, these arealkyltrialkoxysilane and alkyldimethylmonochlorosilane. This means thatthe basic coating chemistry in terms of the surface bonding can betested, while so too can the actual layer performance determined by thealkyl side chains (fluorinated vs. non-fluorinated).

In the following, the spray pattern curves for group I sprays (cf. FIG.9), group II sprays (cf. FIG. 10) and group III sprays (cf. FIG. 11) areshown in graphs.

2.2.3.1.1 Group I Spray Pattern Curve

FIG. 9 shows the group I (“good sprays”) spray curves for the coatednozzles and the uncoated reference. The number of group I spraysdecreases for all test branches to a greater or lesser extent over time,although all the test branches in which coated nozzles are used displaya better spray pattern curve than the uncoated reference. It is notuntil around the end of the test that the spray pattern curves for testbranches C8-OET, C8-Cl and F12C8-Cl approach the reference. In thisregard, the number of group I sprays drops below 20% for these testbranches.

This does not occur with coating reagent F13C8-OET, which showsexcellent performance over the spray pattern curve. Up to the end of thetest, a proportion of almost 80% remained in group I sprays (“goodsprays”). This is an advantage of more than 60% over the other coatingreagents. If this correlated with the coating reagent C8-OET, theadvantage of the perfluorinated side chain of F1308-OET is clear.

The coating reagent C8-OET obtains a similarly poor result towards theend of the test as the two chlorosilanes F1308-Cl and C8-Cl. It isclear, however, that it has a significant advantage over these twocompounds in the preceding test days, taking an intermediate positionbetween F1308-OET and the two chlorosilanes.

Overall, the relatively poor spray performance of the two chlorosilanesis surprising. It is also surprising that, in relation to F1308-Cl, thebenefit of a perfluorinated side chain is not detectable either comparedwith C8-Cl. The fact that C8-Cl provides similar results leads to theassumption that the surface bonding is not stable enough in thechlorosilanes. While they do have an advantage over the uncoatedreference in the first few test days, this lasts only until day 17.

2.2.3.1.2 Group II Spray Pattern Curve

FIG. 10 shows the group II spray curves for the coated nozzles and theuncoated reference. The proportion of group II sprays (“spray patternanomalies”) increases over time to a greater or lesser extent for alltest branches. The reference reaches its maximum as early as test day 4at over 60%, whilst no specific maximum can be identified for the othertest branches. There is a continuous increase of group II sprays overthe test duration. What is also striking is the large advantage of thecoating reagent F1308-OET. At the end of the test, the proportion ofspray pattern anomalies is just 15%, and from day 5 onwards is alwaysbelow the other test branches over the entire test period.

2.2.3.1.3 Group III Spray Pattern Curve

FIG. 11 shows the group III (“jet divergency”) spray curves for thecoated nozzles and the uncoated reference. The figure shows that theproportion of group III sprays also increases to a greater or lesserextent over the time period for all test branches. Towards the end ofthe test, the two chlorosilanes reach a similar rate of group III sprays(almost 60%) as the uncoated reference. Compared with the reference,therefore, the chlorosilanes show only a temporary benefit lasting a fewtest days since the chlorosilanes and the reference already have asimilar number of group III sprays (around 40%) after day 16. In thisview, the coating reagent C8-OET again assumes a position in the middlehaving a group III spray rate of almost 30% at the end of the test. Thecoating reagent F13C8-OET has by far the best spray performance: Lessthan 10% of the atomisers showed a group III spray over all test days.

2.2.3.1.4 Group III Spray Pattern Curve: 10-Day Average Rate Towards theEnd of the Test

The advantage of the coating reagent F1308-OET is particularly clearfrom the 10-day average rate shown in FIG. 15. In the 10-day average,the reference reaches a rate of almost 50% group III sprays. This issimilar to the two chlorosilane test branches, which exhibit a similarlyhigh 10-day average rate of around 50%. The lowest rate of group IIIsprays is achieved by the test branch containing the coating reagentF1308-OET, which achieves a 10-day average rate of less than 5% towardsthe end of the test; this is remarkably better than all the other testbranches. The coating reagent C8-OET also has a significantly better10-day average rate of just around 25%. This coating reagent thusprovides significantly better protection against plaque deposits thanthe alkylchlorosilanes.

Overall, the advantage of alkyltrialkoxysilanes over alkylchlorosilanesis very unmistakeable.

The result of the provocation test using functionalised nozzles showsthat the likelihood of a clogged nozzle can be dramatically reduced whenthe correct coating reagent is used.

For incomprehensible reasons, the alkyldimethylmonochlorosilanesperformed relatively badly and barely brought any benefit to sprayperformance compared with the reference. This was unexpected since thealkyldimethylmonochlorosilanes also exhibit good binding properties inthe literature (cf. Fadeev, A. Y. and T. J. McCarthy, Trialkylsilanemonolayers covalently attached to silicon surfaces: wettability studiesindicating that molecular topography contributes to contact anglehysteresis. Langmuir, 1999. 15(11): pp. 3759-3766). The spray patterncurve over the testing period is no better than the uncoated reference.

Reasons why the alkyldimethylmonochlorosilanes bonded poorly to thesurface can only be hypothesised. One possible critical disadvantage ofalkyldimethylmonochlorosilanes is that this substance class only has onesite for binding to the surface. By comparison, alkyltrialkoxysilaneshave two more coordination sites, which appears to lead to increasedbonding stability. If consideration is also given to the forceconditions in the atomisers used, which can reach a pressure of morethan 200 bar and flow rate of over 130 m/s in the nozzle channel, it maybe that these forces are simply too great for just one coordinationsite, resulting in layer erosion or layer detachment.

2.2.4 Long-Term Performance of1H,1H,2H,2H-Tridecafluorooctyltriethoxysilane in in-Use Tests

In a provocation test, it was investigated how long nozzle blockagescould be avoided by using coated nozzles. To do so, nozzles were coatedwith 1H,1H,2H,2H-tridecafluorooctyltriethoxysilane and tested in aprovocation test in in-use mode 1×2 over a period of 120 days. Overall,60 coated nozzles of nozzle body categories I+II, III and IV were used.

The provocation test is set up as follows:

Coating Reagent:

-   -   Dynasylan® F8261        (=1H,1H,2H,2H-tridecafluorooctyltriethoxysilane) (F1308-OET)    -   Reference (uncoated)

Concentration: 0.03 mol/l

Formulation: as in 1.3.3

Duration of test: Ref.=45 days, F13C8=120 days

Number of inhalers: 60 coated with F13C8-OET, 30 reference (uncoated)

In-use mode: 1×2 strokes/day

Test parameters: Spray pattern according to spray pattern catalogue

2.2.4.1 Group I Spray Pattern Curve

FIG. 13 shows the group I (“good sprays”) spray curves for thelong-duration provocation test. FIG. 13 illustrates the great advantagethe coating has over the uncoated reference. Whereas the reference hadonly around 20% group I sprays (“good sprays”) on test day 45, thecoated nozzles had more than 80%. Even at the end of the test on testday 120, F13C8-OET still had more than 60% of the atomisers producing agroup I spray (“good spray”). As can be seen in the graph, the referencewas stopped on day 45 since the good-spray rate had reached a balancedstate at around 20%.

Within the first few test days, some of the coated atomisers actuallybegan to deviate from a group I spray. This can be traced back to thepresence of coating residues. Over the first few days, therefore, thereference tended to perform slightly better than the devices havingcoated nozzles. This effect lasted until around day 10, after which thenumber of good sprays in the reference began to drop considerably. Inthis case, the reason for this phenomenon at the beginning is the use of“good” and “bad” nozzle categories. In terms of coating residues,category I and II nozzles as well as category III and IV nozzles wereused in this test.

It is very clear from this test that coating solution residues can alsocause group II and group III sprays.

2.2.4.2 Group II Spray Pattern Curve

FIG. 14 shows the group II (“spray anomalies”) spray curves for thelong-duration provocation test. For the reference in particular, thenumber of group II sprays increases very sharply over time. In thisregard, more than 70% group II sprays were already observed on day 20.Looking at the spray pattern curve for the coated nozzles (F1308-OET),it can be seen that a moderate increase in group II sprays was alsoapparent in this case. However, the coated nozzles only had around30-40% group II sprays even at the end of the test on day 120; this isconsiderably lower than the reference.

It is also apparent that spray pattern anomalies (group II sprays)occurred in the devices having coated nozzles as early as on the firsttest day. This is down to the coating residues as mentioned above.Despite the coating, the F1308 devices also showed an increase in groupII sprays after a certain time, which indicates the process of plaquedeposit formation in this case too. Over the spray pattern curve, alarger increase can be seen from around day 40.

In terms of the coating residues, the coated nozzle bodies havingcoating residues can be discarded before being fitted as part of avisual check on the coated nozzle bodies. Discarding these significantlyreduces the spray pattern anomalies for devices having coated nozzles.

2.2.4.3 Group III Spray Pattern Curve

FIG. 15 shows the group III (“jet divergency”) spray curves for thelong-duration provocation test. As can be seen in the figure, very fewgroup III sprays occur overall (batch effects also play a role in thisrespect). When comparing the coated nozzles with the reference, it canbe seen that the reference already showed some group III sprays aftertest day 10, whereas with the coating this occurred for the first timeas of day 70. This means that the coating was able to delay theoccurrence of the first group III sprays for around 60 days.

Under stress conditions, the atomiser batch tested here had a very lownumber of group III sprays from the outset, although a large number ofgroup II sprays were formed very quickly in the reference. Generally,these group II sprays quickly react further to become group III spraysand can thus also be an indicator of nozzle blockages.

2.2.4.4 Group III Sprays: 10-Day Average Rate Towards the End of theTest

FIG. 16 shows the 10-day average rate at the end of the test for thelong-duration provocation test. FIG. 16 again shows a summary of theresults of the spray pattern progression for group Ill sprays. On day45, the reference had a rate of around 5% group III sprays. Bycomparison, the atomisers having coated nozzles had still not shown anygroup III sprays. These occurred sporadically from around day 70. Evenat the end of the test on day 120, the atomiser devices having coatednozzles had a similar 10-day average rate of around 5%.

2.2.4.5 Results for Performance of1H,1H,2H,2H-Tridecafluorooctyltriethoxysilane Nozzle Coatings

The result of the long-duration provocation test using functionalisednozzles shows that the likelihood of a clogged nozzle can bedramatically reduced even over a very long test period. The duration ofthis test was 120 days altogether. The 120 days were derived from apotential 4-month use of the inhaler. For the nozzles coated in thiscase with 1H,1H,2H,2H-tridecafluorooctyltriethoxysilane, a group IIIspray first occurred on test day 70. The reference, on the other hand,already showed the first group III sprays after day 10. This is anadvantage for the coating of 60 days. The coating delayed the appearanceof group III sprays for this long period of time, which is an excellentresult.

What is also striking in this test is that very few group III spraysoccurred over the entire test duration. This is surprising even for theuncoated reference. The reason for this is the atomiser batch itself,which has also demonstrated very few group III sprays in other tests.The incidence of group II and III sprays is dependent on the devicebatch used. However, it is notable in this test that the number of groupII sprays remained very high for a very long time. Generally, the numberof group III sprays increases significantly when the maximum in thegroup II sprays is reached very quickly (i.e. devices having group IIsprays become devices having group III sprays).

The reference was stopped at day 45 since the advantage of the coatingwas already clear and the reference had reached a balanced state. At day70, the inhalers having the coated nozzles also showed the first groupIII sprays. However, the rate of the increase did not match that of theuncoated reference; instead, it rose much more slowly.

2.3. Long-Term Stability of the Coating: Stability Study on CoatedSi/Glass Planar Substrates

A stability study is designed to investigate the effect of differentstress parameters (pH, temperature, storage time) on the layerperformance of 1H,1H,2H,2H-tridecafluorooctyltriethoxysilane. For thispurpose, silicon and glass substrates were coated to threeconcentrations in a plurality of coating approaches and stored over timein ethanolic placebo solution. The samples were each coated to identicalcoating parameters and differed only on account of the concentration ofthe coating solution. The stability of the samples was then assessedusing layer thickness measurements and contact angle measurements.

2.3.1 Stability Study Set-Up

Si/glass planar substrates were coated at the three followingconcentrations: 0.003 mol/l, 0.015 mol/l and 0.03 mol/l. The sampleswere stored in a sealed manner protected from light in polyethylenebottles in an ethanolic placebo solution at pHs of 2.0 and 4.5, and atroom temperature in the laboratory (20° C.±3° C.) and 40° C. in theclimatic test cabinet. For the high coating concentration, the storagetime was 14, 30, 90 and 180 days. The two lower coating concentrationswere stored for just 30 and 180 days. The study parameters aresummarised in Table 7.

TABLE 7 Set-up for Si/glass planar substrate stability study Sample TimeTemper- concentration [days] ature pH [mol/l] Substrate 14 30 90 180 RT40° C. 2.0 4.5 0.03 Si + glass x x x x x x x x 0.015 Si + glass x x x xx x x 0.003 Si + glass x x x x x x Reference x x x x x x x x Reference:x = carried out without silicon/glass substrates

2.3.2 Coating the Si/Glass Planar Substrates

For the stability study, the Si/glass planar substrates were coated inseveral batches in accordance with section.

2.3.3 Storing the Substrates

For the stability study, two ethanolic placebo solutions at pH 2.0 and4.5 were used. On the day the samples were placed into storage, 170 gethanolic placebo solution was placed in each polyethylene bottle. Next,two silicon and glass substrates were added to each bottle using wafertweezers. In doing so, care should be taken to ensure the substrates arepositioned in the bottle such that they do not adhere to one another.Once the bottles are closed, the weight of the entire PE bottle wasdetermined and recorded in order to be able to determine the weight lossdue to the storage when the substrates are removed from storage. Inaddition, reference samples without substrates were also put intostorage for each storage duration, pH and temperature.

2.3.4 Checking the pH and Weight Upon Removal from Storage

On the day the substrates are removed from storage, the weight of the PEbottle was determined again and the weight lost over the storage timethus ascertained. In addition to the weight loss, the pH of the solutionwas also checked. This makes it possible to check whether the PE bottlewas sufficiently tight over the duration of the test and whether the pHhas changed during storage.

2.3.5 Analysing the Stability Study

The stability study was analysed using static contact angle measurementand layer thickness measurements by means of spectroscopic ellipsometry.The values of a sample upon removal from storage were related tostarting values determined beforehand for the contact angle and layerthickness. The starting values were collected using a representativesample that had not been stored and contained samples from each coatingprocess carried out beforehand.

2.3.5.1 Change in the Contact Angle Over the Storage Time

Below, the results in term of the contact angle measurements on siliconand glass are presented.

The tests show a clear concentration effect for the starting values onsilicon. As the coating concentration was increased, a higher contactangle for water and n-dodecane was obtained and a smaller standarddeviation was produced. In each case, 5 droplets of water and 5 dropletsof n-dodecane were measured per substrate. With 10 measurements perdroplet, this resulted in 50 angles.

2.3.5.1.1 Changes to the Contact Angle on Silicon when Stored at Room

Temperature (25° C.) The change in the water contact angle andn-dodecane contact angle on silicon when stored at room temperature wastested. The test results are summarised in Tables 8 and 9.

TABLE 8 Changes to the water contact angle on silicon when stored atroom temperature (25° C.) MTMS Contact angle [°] concentration StartingChange [mmol/l] pH value 14 days 30 days 90 days 180 days 0.03 2.0112.72 1.39 2.07 3.44 7.34 0.03 4.5 112.72 3.05 4.18 5.66 6.97 0.015 2.0108.78 n.d.¹ 4.73 3.25 3.96 0.015 4.5 108.78 n.d.¹ 6.55 3.27 3.19 0.0032.0 101.61 n.d.¹ 1.76 n.d.¹ 7.52 0.003 4.5 101.61 n.d.¹ 0.01 n.d.¹ −1.41¹n.d. = not determined

TABLE 9 Changes to the n-dodecane contact angle on silicon when storedat room temperature (25° C.) MTMS Contact angle [°] concentrationStarting Change [mmol/l] pH value 14 days 30 days 90 days 180 days 0.032.0 68.82 0.51 3.11 4.40 4.82 0.03 4.5 68.82 0.33 3.20 3.51 5.42 0.0152.0 66.40 n.d.¹ −1.71 0.82 1.55 0.015 4.5 66.40 n.d.¹ 0.26 1.59 1.480.003 2.0 61.42 n.d.¹ 6.68 n.d.¹ 5.03 0.003 4.5 61.42 n.d.¹ 2.20 n.d.¹−1.72 ¹n.d. = not determined

The tests show that the water contact angle and the n-dodecane contactangle only vary to a minor extent (x≤10°) over the storage periodconsidered. However, a gradual fall in the contact angle over thestorage period can be seen for the coating concentration 0.003 mol/l.This effect can be detected in both water and dodecane.

It can be stated that the spread in the contact angle at a coatingconcentration of 0.003 mol/l is very high overall. In some cases, it isover 20° and thus conceals potential effects. By comparison, at thecoating concentrations 0.015 mol/l and 0.03 mol/l, very precise valuesare achieved with very low spread. This indicates that a homogeneouscoating is not always achieved at a concentration of 0.003 mol/l.

Since all the average changes for the water and the dodecane contactangle remain below 10°, it can be concluded that, in this case, at mostthere has merely been a change to the layer alteration but no layerdetachment. The water contact angle for an uncoated silicon or glasssubstrate would be at around 30-40°. An activated substrate would beeven more hydrophilic. The water contact angles considered here areabove 100° even after storage.

Detachment of the layer would lead to changes in the water contact angleof well over 50°. This is clearly not the case here.

There was also no general discernible difference between storage at pH2.0 and pH 4.5 (i.e. the coating is acid-resistant in the tested pHregion).

2.3.5.1.2 Changes to the Contact Angle on Silicon when Stored at 40° C.

The change in the water contact angle and n-dodecane contact angle onsilicon when stored in the climatic test cabinet at 40° C. was tested.The test results are summarised in Tables 10 and 11.

TABLE 10 Changes to the water contact angle on silicon when stored at40° C. MTMS Contact angle [°] concentration Starting Change [mmol/l] pHvalue 14 days 30 days 90 days 180 days 0.03 2.0 112.72 0.01 5.20 4.178.13 0.03 4.5 112.72 3.49 3.41 6.74 9.08 0.015 2.0 108.78 n.d.¹ −6.500.13 4.39 0.015 4.5 108.78 n.d.¹ −3.53 3.42 6.34 0.003 2.0 101.61 n.d.¹0.90 n.d.¹ 16.73 0.003 4.5 101.61 n.d.¹ 3.83 n.d.¹ 6.08 ¹n.d. = notdetermined

TABLE 11 Changes to the dodecane contact angle on silicon when stored at40° C. MTMS Contact angle [°] concentration Starting Change [mmol/l] pHvalue 14 days 30 days 90 days 180 days 0.03 2.0 68.82 0.88 2.17 1.737.19 0.03 4.5 68.82 2.29 2.42 5.36 5.93 0.015 2.0 66.40 n.d.¹ −1.71−0.19 1.19 0.015 4.5 66.40 n.d.¹ 0.26 2.11 3.21 0.003 2.0 61.42 n.d.¹−4.68 n.d.¹ 11.67 0.003 4.5 61.42 n.d.¹ 1.67 n.d.¹ 2.21 ¹n.d. = notdetermined

The tests show that the contact angle only varies slightly in terms ofthe stress variables shown, as set out in Table 7 in section 2.3.1. Theaverage change in the water contact angle remains below 10°, even whenthe temperature is increased. A gradual fall in the contact angle overtime was also recorded here at the concentrations 0.015 mol/l and 0.03mol/l, similarly to the values determined at room temperature.

Overall, it can be stated that increasing the temperature does notreduce or alter the hydrophobicity of the substrates either. The data isabsolutely comparable with the values at room temperature. Therefore, notemperature effects can be detected on the silicon substrates.

2.3.5.1.3 Changes to the Contact Angle on Glass when Stored at RoomTemperature (25° C.)

The change in the water contact angle and n-dodecane contact angle onglass when stored at room temperature was tested. The test results aresummarised in Tables 12 and 13.

TABLE 12 Changes to the water contact angle on glass when stored at roomtemperature (25° C.) MTMS Contact angle [°] concentration StartingChange [mmol/l] pH value 14 days 30 days 90 days 180 days 0.03 2.0112.06 2.13 −2.26 −1.00 3.92 0.03 4.5 112.06 −4.31 0.75 −6.21 0.61 0.0152.0 87.41 n.d.¹ −9.10 −14.92 −13.81 0.015 4.5 87.41 n.d.¹ −12.65 −12.05−19.27 0.003 2.0 91.40 n.d.¹ −5.48 n.d.¹ 22.08 0.003 4.5 91.40 n.d.¹−3.65 n.d.¹ 2.03 ¹n.d. = not determined

TABLE 13 Changes to the dodecane contact angle on glass when stored atroom temperature (25° C.) MTMS Contact angle [°] concentration StartingChange [mmol/l] pH value 14 days 30 days 90 days 180 days 0.03 2.0 68.913.74 1.27 2.61 2.79 0.03 4.5 68.91 2.64 5.84 −2.66 1.59 0.015 2.0 47.52n.d.¹ −11.50 −12.20 −2.78 0.015 4.5 47.52 n.d.¹ −14.49 −9.92 −15.510.003 2.0 60.57 n.d.¹ 16.11 n.d.¹ 2.85 0.003 4.5 60.57 n.d.¹ 9.65 n.d.¹6.89 ¹n.d. = not determined

It can be seen that the layer does not detach on glass either. In thesubstrates, the average change in the contact angle also remains below10° at a coating concentration of 0.03 mol/l, as already seen with thesilicon substrates. Looking at the data for the coating concentrations0.003 mol/l and 0.015 mol/l, a very high spread in the values can beseen here too, in particular for the coating concentration 0.003 mol/l.This is similar to the spread on silicon for the same coatingconcentration and also conceals potential effects here.

The results for the coating concentration 0.015 mol/l also display anoticeable feature. Here, the contact angle for water and n-dodecane isgreater than the determined starting value. This trend was measured forall samples, though it is insignificant once standard deviation is takeninto account.

Overall, it can be concluded that no storage effects can be noted forglass substrates either. This also includes the two pHs tested.

2.3.5.1.4 Changes to the Contact Angle on Glass when Stored at 40° C.

The change in the water contact angle and n-dodecane contact angle onglass when stored at 40° C. was tested. The test results are summarisedin Tables 14 and 15.

TABLE 14 Changes to the water contact angle on glass when stored at 40°C. MTMS Contact angle [°] concentration Starting Change [mmol/l] pHvalue 14 days 30 days 90 days 180 days 0.03 2.0 112.06 0.79 −2.19 17.55−1.56 0.03 4.5 112.06 −1.89 2.74 −1.67 −1.08 0.015 2.0 87.41 n.d.¹−17.06 −13.58 −14.47 0.015 4.5 87.41 n.d.¹ −17.54 −18.90 −23.69 0.0032.0 91.40 n.d.¹ −16.71 n.d.¹ 14.21 0.003 4.5 91.40 n.d.¹ −13.74 n.d.¹−16.11 ¹n.d. = not determined

TABLE 15 Changes to the dodecane contact angle on glass when stored at40° C. MTMS Contact angle [°] concentration Starting Change [mmol/l] pHvalue 14 days 30 days 90 days 180 days 0.03 2.0 68.91 2.03 −0.67 13.38−0.03 0.03 4.5 68.91 7.04 2.51 3.96 −1.25 0.015 2.0 47.52 n.d.¹ −17.96−13.12 −13.24 0.015 4.5 47.52 n.d.¹ −17.34 −19.10 −21.52 0.003 2.0 60.57n.d.¹ 12.30 n.d.¹ 0.80 0.003 4.5 60.57 n.d.¹ 4.83 n.d.¹ −3.87 ¹n.d. =not determined

In principle, the values determined for 40° C. are comparable with thoseat room temperature.

Overall, it can be concluded here too that no specific storage effectcan be detected for glass at a temperature of 40° C. This also includesthe two pHs tested 2.0 and 4.5.

2.3.5.2 Effect of Storage on Layer Thickness

Below, the results in term of the layer thickness measurements carriedout on silicon and glass using ellipsometry are presented.

Each substrate was measured three times at the angles 65°, 70° and 75°using spectroscopic ellipsometry.

The sample having the coating concentration 0.003 mol/l stood out interms of their standard deviation in the ellipsometric measurements too.In addition, it can also be seen that as the concentration was increasedfurther, the layer thickness on the silicon substrates did not increaseby a measurable amount. However, this effect can be noted as a trend onglass substrates.

The model assumed for the analysis corresponds to the explanations undersection 1.4.4. The refractive index required for the SAM layer thicknessmeasurement was taken from the literature and is 1.256 (cf. Jung, J.-I.,J. Y. Bae, and B.-S. Bae, Characterization and mesostructure control ofmesoporous fluorinated organosilicate films. Journal of MaterialsChemistry, 2004. 14(13): pp. 1988-1994).

2.3.5.2.1 Changes to the Layer Thickness on Silicon when Stored at RoomTemperature and at 40° C.

The change in the layer thickness on silicon when stored at roomtemperature (25° C.) and at 40° C. was tested. The test results aresummarised in Tables 16 and 17.

TABLE 16 Changes to the layer thickness of the MTMS coating on siliconwhen stored at room temperature (25° C.) MTMS Layer thickness [nm]concentration Starting Change [mmol/l] pH value 30 days 90 days 180 days0.03 2.0 0.93 −0.10 −0.02 −0.06 0.03 4.5 0.93 −0.10 −0.14 −0.11 0.0152.0 1.06 −0.05 0.11 0.16 0.015 4.5 1.06 −0.02 0.03 −0.01 0.003 2.0 1.050.23 n.d.¹ 0.17 0.003 4.5 1.05 0.15 n.d.¹ −0.02 ¹n.d. = not determined

TABLE 17 Changes to the layer thickness of the MTMS coating on siliconwhen stored at 40° C. MTMS Layer thickness [nm] concentration StartingChange [mmol/l] pH value 30 days 90 days 180 days 0.03 2.0 0.93 0.04−0.11 −0.08 0.03 4.5 0.93 0.01 −0.17 −0.14 0.015 2.0 1.06 0.00 0.04 0.070.015 4.5 1.06 −0.08 −0.04 −0.03 0.003 2.0 1.05 0.04 n.d.¹ 0.16 0.0034.5 1.05 0.01 n.d.¹ −0.07 ¹n.d. = not determined

It can be seen that the coating produced on the silicon is very thin.For the starting values, the layer thickness is around 0.7 to 0.9 nm andthus corresponds to the values in the literature (cf. Plueddemann, E.P., Silane Coupling Agents, 2 ed. 1991, New York: Plenum PublishingCorporation). If the spread in the starting values and in the valuesupon removal from storage are taken into account, there is nodiscernible storage effect on the layer thickness. This relates to boththe temperature change from room temperature (25° C.) to 40° C. and thechange in pH from 2.0 to 4.5

As regards the impact of the coating concentration, the aforementionedobservation can be included in the development of the standarddeviation. The spread in terms of the layer thickness also becomes moremoderate as the coating concentration increases, which indicates a morehomogeneous layer formation at higher concentrations.

2.3.5.2.2 Changes to the Layer Thickness on Glass when Stored at RoomTemperature and at 40° C.

The change in the layer thickness on glass when stored at roomtemperature (25° C.) and at 40° C. was tested. The test results aresummarised in Tables 18 and 19.

TABLE 18 Changes to the layer thickness of the MTMS coating on glasswhen stored at room temperature (25° C.) MTMS Layer thickness [nm]concentration Starting Change [mmol/l] pH value 30 days 90 days 180 days0.03 2.0 1.50 0.29 −0.96 −0.26 0.03 4.5 1.50 −1.03 −0.27 −0.27 0.015 2.01.43 −0.10 −0.12 −0.13 0.015 4.5 1.43 −0.26 −0.14 −0.18 0.003 2.0 1.34−0.19 n.d.¹ −0.36 0.003 4.5 1.34 0.16 n.d.¹ −0.28 ¹n.d. = not determined

TABLE 19 Changes to the layer thickness of the MTMS coating on glasswhen stored at 40° C. MTMS Layer thickness [nm] concentration StartingChange [mmol/l] pH value 30 days 90 days 180 days 0.03 2.0 1.50 −0.68−0.49 −0.64 0.03 4.5 1.50 −0.17 −0.28 −0.19 0.015 2.0 1.43 −0.01 −0.24−0.58 0.015 4.5 1.43 −0.35 −0.09 −0.30 0.003 2.0 1.34 0.06 n.d.¹ −0.710.003 4.5 1.34 0.03 n.d.¹ −0.38 ¹n.d. = not determined

It can be seen that the layer thickness of the film generated on glassis significantly greater than on silicon. When the starting values areconsidered, the thickness is approximately 2 nm and is thus more thantwice as thick as the film generated on silicon. In this case, this isdown to a higher density of binding sites (in particular OH bonds)between the generated film and glass (compared with silicon) and/or agreater degree of surface roughness on the glass substrate used(compared with the silicon substrate used).

As has already been demonstrated, there is a discernible concentrationeffect in terms of layer thickness for the coating on glass. As theconcentration of the coating solution increases, the layer thicknesstends to become greater. However, this effect is insignificant and isconcealed by a considerable degree of spread. Even for the highestcoating concentration of 0.03 mol/l, the spread in the starting valuesis still close to around 0.5 nm.

It can therefore be concluded that the layer is detectable and there areno discernible significant changes to the layer thickness due to the pHor temperature. In addition, an effect of the coating concentration onthe layer thickness can be noted. For silicon, the use of higher coatingconcentrations resulted in a moderate spread within the layer thicknessmeasurements. In the case of glass, at high coating concentrations,increasing the concentration tends to lead to higher layer thicknessesbeing detected (this effect was within the standard deviation of themeasurements determined).

2.3.5.3 Stability Study Results

The results of the stability study show that, under the frameworkconditions tested here, the coating can be deemed stable. This isdemonstrated by the values from both the static contact anglemeasurement and the ellipsometric layer thickness measurements.

For the substrates used, complete layer detachment was not identifiedunder any of the tested stress conditions; however, the static contactangle measurements on silicon indeed show that the layer becomesslightly more hydrophilic over the storage period. This correlates wellwith the data from the provocation tests carried out since group IIIsprays occur in coated nozzles after a certain point of the test in thiscase too, which can also be considered an indicator of a possible layerthickness change. The rate of the increase in group III sprays in coatednozzles does not match that of an uncoated reference. In this respect,the increase in group III sprays is always much slower in coatednozzles, indicating the layer effect is still present.

The results of the elliptometric layer thickness measurements alsoindicate a stable layer in all samples. The layer is always detectableand essentially no decrease in the layer thickness is noted.

The results again show that glass and silicon substrates can be coatedsimultaneously in one coating method.

2.4 Effect of Surface Functionalisation on Atomiser Performance

The effect of coated nozzles on atomiser performance was tested. Thenozzles tested were transformed using1H,1H,2H,2H-tridecafluorooctyltriethoxysilane as a coating agent inaccordance with section 1.1.

2.4.1 Effect of the Coating on Priming Behaviour

The effect of coated nozzles on the priming behaviour of the atomiserwas tested.

Priming refers to the initial first operation of the device. In thiscase, the first five strokes immediately after the container used andfilled with provocation solution was inserted were compared in terms ofdelivered mass and metered mass (this was an investigation of thepriming behaviour, it being possible to discern the number of strokes ittakes for the discharged weight to reach its complete or target value).

2.4.1.1 Priming Behaviour Progression: Delivered Mass (DM) and MeteredMass (MM)

The priming behaviour of atomisers comprising coated and uncoated nozzlebodies was tested.

It was found that, in terms of the priming behaviour progression inrelation to delivered mass and metered mass, there was no differencebetween the results from the atomiser test groups having coated nozzlebodies and uncoated nozzle bodies. Therefore, the coating has no impacton the priming behaviour.

2.4.1.2 Effect on the Metering Behaviour: Comparison Between DeliveredMass and Metered Mass in 120-Day in-Use Mode

The effect of coated nozzles on the metering behaviour was tested overan in-use period (provocation mode) of 120 days. The progression of thedelivered mass (DM) and metered mass (MM) for atomisers 9 having coatedand uncoated nozzles was determined. The determination of the deliveredmass and metered mass can be found in section 1.4.3.

2.4.1.2.1 Delivered Mass

The progression of the delivered mass for atomisers 9 having coated anduncoated nozzle bodies was tested over an in-use period of 120 days.

It was clearly shown that, initially, there was no difference betweenthe progression of the delivered mass when using devices having coatedand uncoated nozzle bodies. However, this changed after day 20, afterwhich point the test group of devices not having a coating on the nozzlebody saw an increase in the delivered mass. By day 45, the increase inthe delivered mass reached almost 12 mg and thus remained significantlyabove the average delivered mass for devices having a coating on thenozzle bodies.

This increase was caused by the appearance of spray pattern anomalies inthe group of atomisers not having a coating on the nozzle body. The testwas run in provocation mode and, as it progressed, exhibited more groupII sprays (spray pattern anomalies) and group III sprays in thereference group. Plaque deposits can indeed have an effect on thedelivered mass since they cause deviations in the impact angle (thespray anomalies thus affect the formation of the impact disc in the DJInozzles and thus also influence the aerosol backscattering or formationof residue droplets on the nozzle).

Fundamentally, however, it was found that the two test groups displaytotally comparable metering behaviour. This is only changed by theoccurrence of undesirable spray pattern anomalies.

2.4.1.2.2 Metered Mass

The progression of the metered mass from atomisers having coated anduncoated nozzle bodies was tested over an in-use period of 120 days.

In this case too, the tests carried out did not show any difference inthe progression of the metered mass between atomisers having coated anduncoated nozzle bodies, but rather the results were completelycomparable with one another.

Therefore, it can be concluded that the coating does not have any effecton the metering behaviour of the atomiser. This relates to both thepriming behaviour and the delivered and metered mass.

2.4.2 Effect of Coated Nozzles on Particle Size Distribution

The effect of coated nozzles on particle size distribution was tested.Experiments were carried out on the progression of particle sizedistribution for atomisers having coated and uncoated nozzles. Theparticle size distribution was determined by measurements taken on theAndersen cascade impactor (according to Ph. Eur.) and via laserrefraction (in this case, a Helos BF measurement instrument fromSympatec).

The tested atomisers having coated and uncoated nozzle bodies hadidentical particle size distributions within the accuracy limits of therelevant measurement method.

Experiments were also carried out on the duration of spray of atomisersfitted with coated and uncoated nozzles. In each case, ten devices weretested, with five individual measurements being taken on each one.

It was found that the duration of spray for atomisers having coated anduncoated nozzles did not differ significantly. A duration of spray of0.99±0.03 seconds was determined for coated nozzles, and a duration ofspray of 0.96±0.03 was determined for uncoated nozzles. Therefore,within the measurement accuracy limits, no difference can be discernedin the duration of spray for coated and uncoated nozzles.

2.4.3 Overall Results Regarding the Effect of the Coating on SprayPerformance

No significant difference can be discerned between atomisers havingcoated nozzles and those having uncoated nozzles in terms of the deviceparameters tested. In this respect, the nozzles can be deemed identical.

The results of this performance analysis of coated and uncoated nozzlebodies showed that the coating has no impact on the device parameterstested in this case. This relates to the priming behaviour, the meteringaccuracy, the particle size distribution and the duration of spray.

In light of this, the method tested here for coating nozzles and nozzlebodies fulfils a basic requirement for measures intended to counteractthe phenomenon of clogged nozzles: The possibility of the coatingaffecting the characteristic functional parameters of the atomiser canbe ruled out.

2.5 Testing Other Coating Reagents: Effect of Alkyl Side Chain Length

The tests described above show that coatings based on fluorinatedsilanes, in particular fluoroalkylsilanes are exceptionally suitable forpreventing clogged or blocked nozzles. In addition, some non-fluorinatedsilanes, in particular alkylsilanes, showed promising results.

The tests below are aimed at identifying alternative effective coatingmolecules.

The focus of the following test is analysing the effect of alkyl sidechain length. For this purpose, tests were carried out on coatingmolecules that tend towards the homologous series of alkanes in terms oftheir alkyl side chain. The test again focuses on alkylalkoxysilanes andalkyldimethylchlorosilanes.

The first tests in relation to producing a successful coating will becarried out on the basis of silicon/glass planar substrates. On thebasis of these samples, the homogeneity and hydrophobicity of thecoating will then be characterised by means of static contact anglemeasurements. Using this data, a selection of coating molecules will bedetermined to be used subsequently for a provocation test.

2.5.1 Coating Silicon and Glass Planar Substrates

The substrates are coated according to the procedure known foralkylalkoxysilanes and alkylchlorosilanes from section 1.1. Table 20provides an overview of the coating reagents tested.

TABLE 20 List of the alternative coating reagents tested Coating reagentAbbreviation Description Methyltrimethoxysilane C1 Homologous seriesEthyltrimethoxysilane C2 n-butyltrimethoxysilane C4n-octyltriethoxysilane C8 n-decyltriethoxysilane C10n-dodecyltriethoxysilane C12 Trimethylchlorosilane C1-Cl Homologousseries Ethyldimethylchlorosilane C2-Cl n-butyldimethylchlorosilane C4-Cln-octyldimethylchlorosilane C8-Cl 1H,1H,2H,2H- F13C8-Cl Perfluorinatedperfluorodecyldimethylchlorosilane

2.5.1.1 Screening the Coating Reagents Using Static Contact AngleMeasurement

Table 21 shows the results of the static contact angle measurements forsilicon and glass planar substrates.

TABLE 21 Averages together with standard deviation for water contactangle for additional coating reagents Glass Silicon Standard StandardAverage deviation Average deviation Coating reagent [°] [°] [°] [°]Methyltrimethoxysilane 85.14 1.97 85.85 1.98 Ethyltrimethoxysilane 88.382.08 88.29 1.80 n-butyltrimethoxysilane 88.05 2.13 87.83 0.99n-octyltriethoxysilane 108.35 1.39 103.38 1.15 n-decyltriethoxysilane108.15 2.17 108.96 2.09 n-dodecyltriethoxysilane 108.19 1.89 104.45 2.88Trimethylchlorosilane 91.51 4.77 86.20 6.55 Ethyldimethylchlorosilane88.45 2.05 76.67 1.95 n-butyldimethylchlorosilane 90.46 2.20 81.38 0.88n-octyldimethylchlorosilane 100.99 1.76 88.87 6.301H,1H,2H,2H-perfluoro- 115.36 2.703 110.47 1.158decyldimethylchlorosilane 1H,1H,2H,2H-tridecafluoro- 110.47 2.20 105.402.88 octyltriethoxysilane (reference)

Whereas for alkyltrialkoxysilanes an increase in the contact angle isrecorded as the length of the alkyl chain increases, this observationcannot be made for alkylmonochlorosilanes, in which a non-uniformdevelopment was observed in the water contact angles in relation tochain length.

In almost all the reagents, the contact angle on glass was alwaysslightly higher than on silicon, i.e. for glass surfaces, there was ahigher density of binding sites on the surface than for siliconsurfaces. The largest contact angle was reached by the perfluorinatedcoating reagent F13C8-Cl. All the silicon/glass planar substrates testedshowed stable contact angles with moderate standard deviation. Nosubstrate showed layer detachment.

For the provocation test carried out afterwards using atomiser devices,the following selection was made on the basis of the coating reagentstested here:

-   -   methyltrimethoxysilane (C1)    -   n-octyltriethoxysilane (C8)    -   n-decyltriethoxysilane (C10)    -   n-dodecyltriethoxysilane (C12)    -   trimethylchlorosilane (C1-Cl)    -   n-octyldimethylchlorosilane (C8-Cl)    -   1H,1H,2H,2H-perfluorooctyldimethylchlorosilane (F13C8-Cl)

The selection makes it possible study the effect of the alkyl side chainand the effect of the coating chemistry. In addition, the selectionincludes coating reagents having very high and very low contact angles.Furthermore, this selection makes it possible check whether the contactangle is actually a suitable parameter for assessing whether a reagentis suitable for coating the DJI nozzles in question in order to preventthe phenomena of spray anomalies or jet divergency.

The results of the contact angle study showed that the coating wasfundamentally detectable on all the substrates. All the coating reagentsprovided stable contact angles above 80°, and with a very moderatespread. However, the results also showed that there were significantdifferences in the resultant water contact angle.

In general, tightly packed, methyl-terminated monolayers have watercontact angles of more than 110°. The contact angle becomes smaller asthe molecules are packed less densely in the monolayer. This effect ispresumably demonstrated in this case too in the small-chain alkyl chainsC1, C2 and C2, and is thus representative of both thealkyltriethoxysilanes and alkyldimethylmonochlorosilanes. Overall, thereagents displayed water contact angles of less than 100° on bothsilicon and glass substrates.

It was found that the water contact angle increases as the chain lengthincreases. This effect can be noted in both glass and silicon for thetwo reagent classes tested. In relation to the materials used here, C10and C12 also showed the highest contact angles; this is most likely dueto the higher packing density of the resultant layer. Sieval et al.disclosed that the maximum load of Si (111) is generally only around0.5-0.55 of the molecular modelling simulation (cf. Sieval, A. B., etal., Molecular modeling of covalently attached alkyl monolayers on thehydrogen-terminated Si (111) surface. Langmuir, 2001. 17(7): pp.2172-2181).

2.5.2 Performance of Additional Coating Reagents in a Provocation Test

As already known, the basic method for a provocation test can be takenfrom section 1.3.

The provocation test is set up as follows:

Formulation: as in 1.3.3

Coating:

Alkyltrialkoxysilanes:

-   -   methyltrimethoxysilane (Cl),    -   n-octyltriethoxysilane (C8),    -   n-decyltriethoxysilane (C10),    -   n-dodecyltriethoxysilane (C12)    -   1H,1H,2H,2H-tridecafluorooctyltriethoxysilane (F13-C8)

Alkyldimethylchlorosilanes:

-   -   trimethylchlorosilane (C1-Cl),    -   n-octyldimethylchlorosilane (C8-Cl),    -   1H,1H,2H,2H-perfluorooctyldimethylchlorosilane (F1308-Cl),    -   1H,1H,2H,2H-perfluorodecyldimethylchlorosilane (F17010-Cl)

Concentration: 0.03 mol/l in each case

Number of inhalers: 30 for each reagent and reference

In-use mode: 1×1 stroke/day

Test parameters: Spray pattern according to spray pattern catalogue

Test Duration:

Decyltriethoxysilane (C10) and n-dodecyltriethoxysilane (C12),1H,1H,2H,2H-tridecafluorooctyltriethoxysilane (F13-C8): 120 days, allother reagents 28 days

2.5.2.1 Group I Spray Pattern Curve

FIG. 17 shows the group I (“good sprays”) spray curves for the coatednozzles and the uncoated reference.

The figure shows that the long-chain alkylalkoxysilanes ensured a highnumber of group I sprays (“good sprays”) for a long period of time,whereas all the other coating reagents showed no advantage over theuncoated reference. Within the alkylalkoxysilanes tested here, C12(n-dodecyltriethoxysilane) showed the best results. In this test, iteven had a slight advantage over the perfluorinated F1308(1H,1H,2H,2H-tridecafluorooctyltriethoxysilane). The alkylmonochlorosilanes also performed relatively poorly again in this test.The test result from section 2.2.3 is thus confirmed and can even beextended to cover fluorinated compounds. In this test too, there was noadvantage over the uncoated reference.

This therefore shows that the best spray performance is ensured bycoatings having an alkyltrialkoxysilane (both fluorinated andnon-fluorinated) having a long side chain (i.e. in this case by C₁₀ andC₁₂ chain lengths tested here).

2.5.2.2 Group II Spray Pattern Curve

FIG. 18 shows the group II spray curves (spray pattern anomalies) forthe coated nozzles and the uncoated reference.

FIG. 18 very clearly shows that the long-chain alkylalkoxysilanesproduced significantly fewer group II sprays than the chlorosilanes orshort-chain alkylalkoxysilanes. It can also be seen here that both theshort-chain alkoxysilanes and all the chlorosilanes barely brought anybenefit compared with the uncoated reference. The long-chainalkylalkoxysilanes had a clear advantage over all the other reagentstested.

2.5.2.3 Group III Spray Pattern Curve

FIG. 19 shows the group III spray (“jet divergency”) curves for thecoated nozzles and the uncoated reference.

Examining the group III spray curve also confirms the idea gained fromthe previous spray pattern curves. The long-chain alkylalkoxysilanes didnot once pass the 20% mark over 120 days of in-use time, whereas all theother reagents tested already exceeded this level after around 20 days.

2.5.2.4 Group III Sprays: 10-Day Average Rate Towards the End of theTest

The advantage that alkylalkoxysilanes have over thealkylmonochlorosilanes is particularly evident again when examining the10-day average rate of the group III sprays, as shown in FIG. 20.

FIG. 20 shows the 10-day average rate of group III sprays for thealternative coating reagents after day 28. In this case, the uncoatedreference reached a rate of around 40% group III sprays. The coatingsusing Cl (methyltrimethoxysilane), F1308-Cl(1H,1H,2H,2H-perfluorooctyldimethylchlorosilane) and F17010-Cl(1H,1H,2H,2H-perfluorodecyldimethylchlorosilane) are similarly poor.They show no advantage in terms of their coating. The aforementionedcoating reagents F1308 (1H,1H,2H,2H-tridecafluorooctyltriethoxysilane),C10 (n-decyltriethoxysilane) and C12 (n-dodecyltriethoxysilane) achievevery good performance. For the cartridge period shown here (28-daymode), F1308 (1H,1H,2H,2H-tridecafluorooctyltriethoxysilane) and C12(n-dodecyltriethoxysilane) was able to largely prevent the occurrence ofgroup III sprays.

The results show very good performance for the alkyltrialkoxysilanegroup. The relatively poor performance of alkyl monochlorosilanes issurprising, all the more so since stable contact angles were achieved inthe study carried out previously. No member of the group of testedalkylchlorosilanes could reach a group III spray rate of less than 10%.This is in contrast to the alkyltrialkoxysilanes, three members of whichachieved a value of 5% for the 10-day average group III spray rate.

2.5.2.5 Results of the Provocation Test

As the results of the provocation test show, thealkyldimethylmonochlorosilanes performed relatively poorly, similarly toin section 2.2.3. For the alkyldimethylmonochlorosilanes, the 10-dayaverage group III spray rate was much higher than the longer-chainalkyltrialkoxysilanes. Surprisingly, in this test methyltrimethoxysilanealso showed similar performance to the alkyldimethylmonochlorosilanes.

The reasons for the poor performance of methyltrimethoxysilane areunclear. However, the spray pattern curve showed that the progressionwas very similar to the range of the uncoated reference over the entireduration of the test.

One possible explanation for the poor result for methyltrimethoxysilanecould be an absent or insufficiently stable coating, or inadequatepacking density.

The alkylmonochlorosilanes had a similar curve to the uncoatedreference, although some members of the group did indeed show a slightlayer effect. Looking at the 10-day average rate for group III sprays, aslight effect can be identified for trimethylchlorosilane (C1-Cl) orn-octyldimethylmonochlorosilane (C8-Cl).

The alkyltrialkoxysilanes have two sites more than thealkylmonochlorosilanes for coordinating with the surface. Therefore,they are bound to the surface much more strongly than thealkyldimethylmonochlorosilanes. This would explain the systematicdifference between the alkylmonochlorosilanes and thealkyltrialkoxysilanes. However, this possible explanation does not applyto the poor performance of methyltrialkoxysilane since this reagent alsohas three sites for coordinating with the surface. Layer erosion or theaforementioned effect of the alkyl chain length on the packing densityare assumed here too.

The provocation tests showed that n-decyltriethoxysilane (C10) andn-dodecyltriethoxysilane (C12) were well suited as coating reagents.They display similarly good results in their spray pattern curves as1H,1H,2H,2H-tridecafluorooctyltriethoxysilane (F1308). Examining the10-day average rate, it can be seen that n-dodecyltriethoxysilane (C12)was even slightly better. These results show that non-fluorinatedalkylsilanes are a serious alternative to fluorinated silanes. This issurprising but fluoroalkylsilanes generally do produce the betteranti-adhesion effect (cf. Giessler, S., E. Just, and R. Stôrger,Easy-to-clean properties—Just a temporary appearance, Thin Solid Films,2006. 502(1): pp. 252-256). However, the data from the provocation testshows that a long alkyl chain length in the range of 010 and C12 wassufficient.

The data collected here also leads to the conclusion that a higher watercontact angle alone is not necessarily an indicator of an effectivecoating reagent. In the previous study, the perfluorinated chlorosilaneF17010-Cl had showed excellent contact angles of around 110° butperformed very badly in the subsequent provocation test. Therefore, itis not possible to use the contact angle alone to deduce the sprayperformance in the provocation test, since the stability of the coatingand its packing density also have to be considered. However, a highcontact angle as defined by Ishizaki et al. can indicate a high packingdensity.

2.5.2.6 Yield of Category I Nozzles from Coating with AlternativeCoating Reagents

FIG. 21 shows the results of the microscopic analysis of the coatednozzle bodies in accordance with the nozzle body categorisationcatalogue.

It can be seen in FIG. 21 that the coating reagent F1308(1H,1H,2H,2H-tridecafluorooctyltriethoxysilane) generates the cleanestnozzles under the laboratory conditions tested. More than 90% of thenozzles tested here were classed as category I. The yield of category Inozzles is only around 25% for C12 (n-dodecyltriethoxysilane), whichactually performed better than Dynasylan® F8261 in the provocation test.C10 (n-decyltriethoxysilane) also achieves a very good category I nozzleyield of around 55%.

1H,1H,2H,2H-tridecafluorooctyltriethoxysilane generates the most cleancategory I nozzles by far. In this test, the yield was surprisingly highat 90% and was achieved by additionally separating the nozzles at thedrying phase before tempering.

In principle, the yield of clean nozzles could be increased further byusing additional automated process steps. This could be done, forexample, by using an aforementioned spin rinse dryer, which expelsresidual solution from the nozzle by means of rotation. Alternatively oradditionally, rinsing processes, e.g. using alcoholic solvents, can becarried out. This should further increase the yield of clean nozzlessince much less residual solution is present in the nozzle bodies whenthey are dried further.

2.5.2.7 Overall Results in Terms of Additional Coating Reagents

In conclusion, it is evident that the best results are achieved using along-chain alkylalkoxysilane. In this test, good alternatives to thefluorinated compounds were found, namely n-decyltriethoxysilane (C10)and n-dodecyltriethoxysilane (C12).

LIST OF REFERENCE NUMERALS

1 microstructured component 2 inlet opening 3 outlet opening 4 channels5 fine filter 6 plenary chamber 7 column structure 8 coating 9 atomiser10 liquid 11 aerosol 12 pressure chamber 13 upper housing part 14 innerhousing part 15 lower housing part 16 container 17 mainspring 18pressure generator 19 locking ring 20 button 21 tubular piston 22 returnvalve 23 mount 24 meter 25 filter system

1. A method for modifying a surface of a microstructured componentcomprising: contacting the surface of the microstructured component witha modification reagent, thereby modifying the properties of the surfaceby the chemical and/or physical interaction between the microstructuredcomponent surface and the modification reagent, wherein the modificationreagent comprises at least one modifier selected from the groupconsisting of: silanes, siloxanes, polysiloxanes and/or siliconates andmixtures thereof, and wherein the at least one modifier is at aconcentration of from 0.001 to 2 mol/l based on the modificationreagent.
 2. The method according to claim 1, wherein the modifier is asiloxane selected from the group consisting of: alkylsiloxanes,alkylalkoxysiloxanes, arylsiloxanes and arylalkoxysiloxanes and mixturesthereof, in particular alkylsiloxanes and alkylalkoxysiloxanes andmixtures thereof, and is preferably an alkylalkoxysiloxane.
 3. Themethod according to claim 1, wherein the modifier is a silane havingorganic C₁-C₂₀ groups, in particular C₈-C₁₈ groups, preferably C₁₀-C₁₆groups.
 4. The method according to claim 3, wherein the silane has thegeneral formula I:R¹ _(4-(n+m))SiR² _(m)X_(n)  (I), wherein R¹=alkyl, in particular C₁-C₂₀alkyl, preferably C₈-C₁₈ alkyl, preferably C₁₀-C₁₆ alkyl; aryl, inparticular C₆-C₂₀ aryl, preferably C₆-C₁₀ aryl; olefin, in particularterminal olefin, preferably C₂-C₂₀ olefin, preferably C₈-C₁₈ olefin,particularly preferably C₁₀-C₁₆ olefin; fluoroalkyl, in particularC₁-C₂₀ fluoroalkyl, preferably C₈-C₁₈ fluoroalkyl, preferably C₁₀-C₁₆fluoroalkyl, in particular comprising 1 to 40 fluorine atoms, preferably5 to 35 fluorine atoms, preferably 10 to 30 fluorine atoms; fluoroaryl,in particular C₆-C₂₀ fluoroaryl, preferably C₆-C₁₀ fluoroaryl, inparticular comprising 3 to 20 fluorine atoms, preferably 5 to 20fluorine atoms; fluoroolefin, in particular terminal fluoroolefin,preferably C₂-C₂₀ fluoroolefin, preferably C₈-C₁₈ fluoroolefin,particularly preferably C₁₀-C₁₆ fluoroolefin, in particular comprising 1to 30 fluorine atoms, preferably 3 to 25 fluorine atoms, preferably 5 to25 fluorine atoms; R²=alkyl, in particular C₁-C₃ alkyl, preferablymethyl; X=halide, in particular chloride and/or bromide, preferablychloride; alkoxy, in particular C₁-C₆ alkoxy, particularly preferablyC₁-C₄ alkoxy, most preferably C₁ and/or C₂ alkoxy; and n=1 to 3, inparticular 3, and m=0 to 2, in particular 0 or 2, preferably
 0. 5. Themethod according to claim 1, wherein the silane comprises three reactivechemical functions and/or groups, in particular three hydrolysablechemical functions and/or groups, and is preferably a trialkoxysilane.6. The method according to claim 1, wherein the silane is selected fromfluoroalkyltrialkoxysilanes, the silane in particular being 1H,1H,2H,2H-tridecafluorooctyltriethoxysilane.
 7. The method according toclaim 1, wherein the silane is an alkyltrialkoxysilane, in particularselected from the group consisting of C₁₂ alkyltrialkoxysilanes, C₁₄alkyltrialkoxysilanes and C₁₆ alkyltrialkoxysilanes and mixturesthereof.
 8. The method according to claim 1, wherein the modifier isdried and/or hardened after being brought into contact with, inparticular applied to, the component. 9-10. (canceled)
 11. The methodaccording to claim 1, wherein the surface of the microstructuredcomponent is activated before the surface is brought into contact withthe modification reagent.
 12. The method according to claim 8, whereinthe excess modification reagent is removed before or after the methodstep of drying and/or hardening, in particular after the method step ofdrying and/or hardening, by treating the component in a spin rinsedryer.
 13. The method according to claim 1, further comprising: the stepof determining the quality of the surface modification. 14-15.(canceled)
 16. The method according to claim 1, wherein themicrostructured component comprises glass, in particular silicate glass,preferably quartz glass and/or borosilicate glass, preferablyborosilicate glass. 17-27. (canceled)
 28. The method according to claim1, wherein the entire surface of the microstructured component ismodified. 29-47. (canceled)
 48. The method according to claim 1, furthercomprising treating the microstructured component with ultrasound atleast intermittently, in particular at fixed intervals, and preferablyduring the step of contacting the surface with the modification reagent.49. A method for modifying a surface of a microstructured component,comprising: (a) activating the surface of a microstructured component,(b) contacting the microstructured component with a modification reagentcontaining at least one modifier, (c) drying and/or hardening themodifier, and (d) determining the quality of the surface modification.50-61. (canceled)
 62. A microstructured component comprising a surfacemodification, in particular a coating, obtainable according to claim 1.63. A microstructured component, in particular a nozzle system,preferably for use in a microfluidic system, comprising at least oneinlet opening, at least one outlet opening and inner surfaces formed bymicrostructures, characterised in that the inner surfaces are modified,in particular coated, at least in part.
 64. (canceled)
 65. Themicrostructured component according to claim 63, characterised in thatthe outer surface of the component is modified, in particular coated, inparticular in the region of the outlet opening.
 66. The microstructuredcomponent according to claim 63, characterised in that the surface ofthe component is modified to be rendered hydrophobic, in particular ishydrophobed. 67-76. (canceled)
 77. A discharge apparatus, in particularan atomiser, for fluids, in particular for medicinal liquids, preferablyliquid medicinal products, comprising at least one microstructuredcomponent according to claim
 62. 78. The discharge apparatus accordingto claim 77, comprising at least one liquid medicinal product.
 79. Thedischarge apparatus according to claim 77, characterised in that themedicinal product is a dispersion or solution of at least onepharmaceutical active ingredient. 80-84. (canceled)
 85. A method forassessing the surface modification of a microstructured component,characterised in that a provocation solution is repeatedly conductedthrough the microstructured component, in particular at high pressure,and the flow behaviour of the provocation solution as it exits themicrostructured component is observed. 86-92. (canceled)